SH3YL1

Summary

SH3YL1 (SH3 and SYLF domain containing 1, HGNC:29546) is a protein-coding gene on chromosome 2p25.3, encoding SH3 domain-containing YSC84-like protein 1 (Q96HL8).

Enables phosphatase binding activity and phosphatidylinositol binding activity. Predicted to be involved in regulation of ruffle assembly. Predicted to act upstream of or within phosphatidylinositol biosynthetic process. Located in ruffle membrane.

Source: NCBI Gene 26751 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 78 total
• MANE Select transcript: NM_015677

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29546
Approved symbol	SH3YL1
Name	SH3 and SYLF domain containing 1
Location	2p25.3
Locus type	gene with protein product
Status	Approved
Aliases	Ray, DKFZP586F1318
Ensembl gene	ENSG00000035115
Ensembl biotype	protein_coding
OMIM	617314
Entrez	26751

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 19 protein_coding, 14 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000356150, ENST00000402632, ENST00000403657, ENST00000403658, ENST00000403712, ENST00000405430, ENST00000415368, ENST00000431160, ENST00000451005, ENST00000454318, ENST00000460974, ENST00000462719, ENST00000463865, ENST00000465733, ENST00000468321, ENST00000471948, ENST00000472012, ENST00000472861, ENST00000473104, ENST00000475027, ENST00000477707, ENST00000479739, ENST00000481932, ENST00000488044, ENST00000488979, ENST00000497051, ENST00000602998, ENST00000605370, ENST00000626873, ENST00000890690, ENST00000890691, ENST00000936192, ENST00000936193, ENST00000971970, ENST00000971971, ENST00000971972

RefSeq mRNA: 4 — MANE Select: NM_015677 NM_001159597, NM_001282682, NM_001282687, NM_015677

CCDS: CCDS42646, CCDS54332, CCDS62841, CCDS62842

Canonical transcript exons

ENST00000356150 — 10 exons

Exon	Start	End
ENSE00001537031	218144	219001
ENSE00002148326	263984	264032
ENSE00003491689	224864	224920
ENSE00003493244	253005	253115
ENSE00003545678	249731	249844
ENSE00003571637	234160	234272
ENSE00003663640	229966	230044
ENSE00003669019	247538	247602
ENSE00003670884	231023	231191
ENSE00003685079	233101	233229

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5450 / max 140.1552, expressed in 1525 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26622	4.4438	500
26624	2.8713	1195
26623	0.1978	96
202054	0.0322	9

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
nephron tubule	UBERON:0001231	99.15	gold quality
parotid gland	UBERON:0001831	99.02	gold quality
upper leg skin	UBERON:0004262	98.82	gold quality
body of pancreas	UBERON:0001150	98.69	gold quality
hair follicle	UBERON:0002073	98.67	gold quality
palpebral conjunctiva	UBERON:0001812	98.66	gold quality
pancreas	UBERON:0001264	98.07	gold quality
kidney epithelium	UBERON:0004819	97.98	gold quality
colonic mucosa	UBERON:0000317	97.64	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.62	gold quality
jejunal mucosa	UBERON:0000399	97.54	gold quality
tongue squamous epithelium	UBERON:0006919	97.49	gold quality
oral cavity	UBERON:0000167	97.35	gold quality
esophagus squamous epithelium	UBERON:0006920	97.29	gold quality
adult mammalian kidney	UBERON:0000082	97.19	gold quality
kidney	UBERON:0002113	97.18	gold quality
bronchial epithelial cell	CL:0002328	97.14	gold quality
renal medulla	UBERON:0000362	97.14	gold quality
skin of hip	UBERON:0001554	97.10	gold quality
islet of Langerhans	UBERON:0000006	96.98	gold quality
mammalian vulva	UBERON:0000997	96.97	gold quality
renal glomerulus	UBERON:0000074	96.86	gold quality
rectum	UBERON:0001052	96.79	gold quality
endometrium	UBERON:0001295	96.79	gold quality
amniotic fluid	UBERON:0000173	96.77	gold quality
nasal cavity mucosa	UBERON:0001826	96.72	gold quality
epithelium of bronchus	UBERON:0002031	96.72	gold quality
metanephros	UBERON:0000081	96.68	gold quality
bronchus	UBERON:0002185	96.66	gold quality
seminal vesicle	UBERON:0000998	96.64	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	51.41
E-MTAB-8410	yes	43.97
E-MTAB-10553	yes	26.76
E-HCAD-10	yes	23.67
E-HCAD-1	yes	18.95
E-ANND-3	yes	14.51
E-HCAD-9	yes	12.22
E-GEOD-100618	no	182.18

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting SH3YL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-5571-5P	99.49	66.99	1764

Literature-anchored findings (GeneRIF, showing 6)

• results provide new insight into the SH3YL1 molecular mechanism of dorsal ruffle formation and its regulation by phosphoinositide metabolism (PMID:21624956)
• SH3YL1 promotes Dock4-mediated cell migration and promotes Dock4-mediated Rac1 activation. (PMID:24508479)
• a novel AR-interacting protein, Src homology 3 (SH3)-domain containing, Ysc84-like 1 (SH3YL1), whose interaction with the receptor is dependent upon this polyproline domain, was identified. (PMID:26305679)
• This study shows that SH3YL1 cooperates with ESCRT-I in the sorting and degradation of the EGF receptor. (PMID:31492760)
• The analyses of variants in theACP1-SH3YL1locus derived from whole exome sequencing data showed an association of several correlatedSNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotypeof theAPC1gene, which is well known for its functional role (PMID:31686588)
• SH3YL1 protein as a novel biomarker for diabetic nephropathy in type 2 diabetes mellitus. (PMID:33223406)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3yl1	ENSDARG00000074393
mus_musculus	Sh3yl1	ENSMUSG00000020669
rattus_norvegicus	Sh3yl1	ENSRNOG00000005522

Protein

Protein identifiers

SH3 domain-containing YSC84-like protein 1 — Q96HL8 (reviewed: Q96HL8)

All UniProt accessions (7): C9J4Z8, C9JJI3, Q96HL8, F5GYQ6, H7C1B8, H7C499, S4R3I7

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with SH3D19.

Similarity. Belongs to the SH3YL1 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q96HL8-1	1	yes
Q96HL8-2	2
Q96HL8-3	3
Q96HL8-4	4
Q96HL8-5	5

RefSeq proteins (4): NP_001153069, NP_001269611, NP_001269616, NP_056492* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR007461	Ysc84_actin-binding	Domain
IPR033643	SYLF_SH3YL1-like	Domain
IPR035511	SH3YL1_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR051702	SH3_domain_YSC84-like	Family

Pfam: PF04366, PF14604

UniProt features (17 total): strand 4, splice variant 4, sequence conflict 3, compositionally biased region 2, chain 1, domain 1, helix 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2D8H	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HL8-F1	73.18	0.28

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 182 (showing top): chr2p25, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_REGULATION_OF_RUFFLE_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOCC_RUFFLE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, ONKEN_UVEAL_MELANOMA_UP, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP

GO Biological Process (2): phosphatidylinositol biosynthetic process (GO:0006661), regulation of ruffle assembly (GO:1900027)

GO Molecular Function (3): phosphatase binding (GO:0019902), phosphatidylinositol binding (GO:0035091), protein binding (GO:0005515)

GO Cellular Component (1): ruffle membrane (GO:0032587)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
biosynthetic process	1
phosphatidylinositol metabolic process	1
ruffle assembly	1
regulation of plasma membrane bounded cell projection assembly	1
enzyme binding	1
anion binding	1
binding	1
ruffle	1
cell projection membrane	1
leading edge membrane	1

Protein interactions and networks

STRING

958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3YL1	WASL	O00401	621
SH3YL1	ALKAL2	Q6UX46	605
SH3YL1	DOCK4	Q8N1I0	582
SH3YL1	FAM110C	Q1W6H9	542
SH3YL1	SMAP2	Q8WU79	525
SH3YL1	ACP1	P24666	524
SH3YL1	SNTG2	Q9NY99	483
SH3YL1	SH3PXD2B	A1X283	481
SH3YL1	ARHGEF38	Q9NXL2	473
SH3YL1	CYBA	P13498	468
SH3YL1	EFCAB10	A6NFE3	447
SH3YL1	MAL2	Q969L2	441
SH3YL1	TMEM53	Q6P2H8	413
SH3YL1	ARHGAP26	Q9UNA1	394
SH3YL1	RUNDC3B	Q96NL0	388

IntAct

29 interactions, top by confidence:

A	B	Type	Score
VPS37B	SH3YL1	psi-mi:“MI:0915”(physical association)	0.780
SH3YL1	VPS37B	psi-mi:“MI:0915”(physical association)	0.780
SH3YL1	GFAP	psi-mi:“MI:0915”(physical association)	0.670
SH3D19	SH3YL1	psi-mi:“MI:0915”(physical association)	0.670
GFAP	SH3YL1	psi-mi:“MI:0915”(physical association)	0.670
SH3YL1	SH3D19	psi-mi:“MI:0915”(physical association)	0.670
SH3YL1	ZBTB7B	psi-mi:“MI:0915”(physical association)	0.560
SH3YL1	PIK3C2B	psi-mi:“MI:0914”(association)	0.530
SH3YL1		psi-mi:“MI:0915”(physical association)	0.370
SH3YL1	VPS37B	psi-mi:“MI:0915”(physical association)	0.000
SH3YL1	SH3D19	psi-mi:“MI:0915”(physical association)	0.000
SH3D19	SH3YL1	psi-mi:“MI:0915”(physical association)	0.000
SYNJ1	SH3YL1	psi-mi:“MI:0915”(physical association)	0.000
SH3YL1	VIM	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): SH3YL1 (Two-hybrid), ZBTB7B (Two-hybrid), VPS37B (Two-hybrid), SH3D19 (Two-hybrid), SH3YL1 (Two-hybrid), VPS37B (Two-hybrid), SH3YL1 (Two-hybrid), SH3D19 (Affinity Capture-MS), PIK3C2B (Affinity Capture-MS), SH3YL1 (Affinity Capture-RNA), AR (Affinity Capture-Western), AR (Reconstituted Complex), HELZ (Two-hybrid), SH3D19 (Two-hybrid), SH3YL1 (Reconstituted Complex)

ESM2 similar proteins: A1CTI3, A1DMX4, A3GEV2, A5DEZ5, A5E032, A6ZKU1, A7A261, A7TKW4, B0BNA1, B0Y7W2, B8NNK9, O08641, O13736, O43125, O74786, O94601, P0CO64, P0CO65, P0CP88, P0CP89, P0CR70, P0CR71, P27692, P32790, P32793, P43603, Q0CHZ8, Q2H9L1, Q2UMV7, Q3SZ01, Q4P3H6, Q4WMP0, Q5ADX5, Q5ALX3, Q5AVZ7, Q5JKF2, Q5RAQ2, Q6BKU3, Q6BZG0, Q6C5G0

Diamond homologs: A1CEK6, A1DFN5, A1DFP5, A2QW93, A2QWA2, A3LXQ8, A4FU49, A4RF61, A6QLK6, B0BNA1, F4KAU9, O08641, O14964, O35179, O35180, O35413, O35964, O43125, O74749, O80910, O94875, P07751, P0CR78, P0CR79, P10569, P19878, P29355, P38753, P62993, P62994, P87379, Q06449, Q07883, Q08012, Q0CJU8, Q0CJV3, Q0U4Z8, Q0U6X7, Q0V8S0, Q15080

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

78 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2774 predictions. Top by Δscore:

Variant	Effect	Δscore
2:231016:A:C	donor_gain	1.0000
2:231021:A:AC	donor_gain	1.0000
2:231022:C:CC	donor_gain	1.0000
2:231031:T:A	donor_gain	1.0000
2:231032:C:A	donor_gain	1.0000
2:231040:C:CA	donor_gain	1.0000
2:231041:C:A	donor_gain	1.0000
2:231085:A:AC	donor_gain	1.0000
2:231086:C:CC	donor_gain	1.0000
2:231192:C:CC	acceptor_gain	1.0000
2:231904:G:C	donor_gain	1.0000
2:233089:A:C	donor_gain	1.0000
2:233099:A:AC	donor_gain	1.0000
2:233100:C:CC	donor_gain	1.0000
2:233100:CTTT:C	donor_gain	1.0000
2:233103:T:A	donor_gain	1.0000
2:233136:C:A	donor_gain	1.0000
2:233169:TG:T	donor_gain	1.0000
2:234153:AACTC:A	donor_loss	1.0000
2:234154:ACTCA:A	donor_loss	1.0000
2:234155:CTCA:C	donor_loss	1.0000
2:234156:TCA:T	donor_loss	1.0000
2:234157:CAC:C	donor_loss	1.0000
2:234158:ACC:A	donor_loss	1.0000
2:249729:A:AC	donor_gain	1.0000
2:249730:C:CC	donor_gain	1.0000
2:249732:T:TA	donor_gain	1.0000
2:249852:C:CT	acceptor_gain	1.0000
2:249853:G:C	acceptor_gain	1.0000
2:249853:G:GC	acceptor_gain	1.0000

AlphaMissense

2195 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:247600:A:G	W77R	0.999
2:247600:A:T	W77R	0.999
2:249760:C:T	G66E	0.998
2:249761:C:A	G66W	0.998
2:249775:G:T	A61D	0.998
2:218873:A:G	W323R	0.997
2:218873:A:T	W323R	0.997
2:249817:A:G	L47P	0.997
2:249820:C:T	G46D	0.997
2:249821:C:G	G46R	0.997
2:218839:A:G	F334S	0.996
2:218867:C:G	G325R	0.996
2:218867:C:T	G325R	0.996
2:218876:A:G	W322R	0.996
2:218876:A:T	W322R	0.996
2:234179:C:G	A129P	0.996
2:234250:A:G	L105P	0.996
2:247545:C:T	G95E	0.996
2:247572:G:T	A86D	0.996
2:247598:C:A	W77C	0.996
2:247598:C:G	W77C	0.996
2:249814:G:T	A48E	0.996
2:249826:G:T	A44D	0.996
2:253010:A:T	I36N	0.996
2:218905:A:T	V312D	0.995
2:234259:A:T	V102E	0.995
2:249766:C:T	G64D	0.995
2:249827:C:G	A44P	0.995
2:218866:C:T	G325E	0.994
2:218874:C:A	W322C	0.994

dbSNP variants (sampled 300 via entrez): RS1000048078 (2:257193 C>T), RS1000163180 (2:231611 A>C,G), RS1000213604 (2:242597 G>A), RS1000250784 (2:231954 A>G), RS1000313151 (2:235126 C>T), RS1000354134 (2:239307 T>C), RS1000367002 (2:236239 C>T), RS1000433134 (2:251304 G>A), RS1000564191 (2:242334 AGTGT>A), RS1000586644 (2:233399 T>G), RS1000705728 (2:237671 G>C), RS1000763828 (2:240351 A>G), RS1000807314 (2:256960 C>T), RS1000864570 (2:224594 G>A), RS1000936235 (2:248000 A>G)

Disease associations

OMIM: gene MIM:617314 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002616_7	Mitochondrial DNA levels	4.000000e-06
GCST003542_30	Night sleep phenotypes	5.000000e-06
GCST005950_2	Body mass index x sex x age interaction (4df test)	5.000000e-75
GCST005951_193	Body mass index	1.000000e-72
GCST005952_2	Body mass index (age>50)	2.000000e-30
GCST005954_1	Body mass index x age interaction	4.000000e-07
GCST006611_66	HDL cholesterol	5.000000e-08
GCST007991_5	Large artery stroke	6.000000e-06
GCST008058_186	Estimated glomerular filtration rate	1.000000e-11
GCST008059_246	Estimated glomerular filtration rate	2.000000e-10
GCST008062_103	Blood urea nitrogen levels	2.000000e-07
GCST010002_382	Refractive error	6.000000e-25
GCST010241_369	Apolipoprotein A1 levels	3.000000e-10
GCST010242_343	HDL cholesterol levels	6.000000e-13
GCST012226_432	Waist circumference adjusted for body mass index	2.000000e-12
GCST012226_433	Waist circumference adjusted for body mass index	2.000000e-09
GCST012231_165	A body shape index	3.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	5
bisphenol A	decreases methylation, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
afuresertib	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	affects cotreatment, increases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	decreases expression	1
Calcitriol	affects cotreatment, increases expression	1
Cosmetics	affects cotreatment, increases expression	1
Coumestrol	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression, affects cotreatment	1
Flame Retardants	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.