NHSL1

Summary

NHSL1 (NHS like 1, HGNC:21021) is a protein-coding gene on chromosome 6q24.1, encoding NHS-like protein 1 (Q5SYE7).

Predicted to be involved in cell differentiation.

Source: NCBI Gene 57224 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 281 total
• MANE Select transcript: NM_001144060

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21021
Approved symbol	NHSL1
Name	NHS like 1
Location	6q24.1
Locus type	gene with protein product
Status	Approved
Aliases	bA43P8.1, KIAA1357
Ensembl gene	ENSG00000135540
Ensembl biotype	protein_coding
OMIM	620171
Entrez	57224

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000342260, ENST00000343505, ENST00000426841, ENST00000427025, ENST00000468095, ENST00000479393, ENST00000491526, ENST00000533765, ENST00000534376

RefSeq mRNA: 2 — MANE Select: NM_001144060 NM_001144060, NM_020464

CCDS: CCDS47487, CCDS55063

Canonical transcript exons

ENST00000343505 — 8 exons

Exon	Start	End
ENSE00001370074	138447001	138447193
ENSE00001378871	138441983	138442114
ENSE00001391269	138430393	138433680
ENSE00001731373	138422043	138424816
ENSE00001764562	138429711	138429843
ENSE00003531909	138499233	138499494
ENSE00003594645	138473306	138473433
ENSE00003599346	138496219	138496371

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 98.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6937 / max 348.8131, expressed in 1375 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75923	2.0027	658
75924	1.8470	671
75908	1.7950	926
75916	1.7609	302
75928	1.2234	329
75922	1.0811	511
75919	0.7579	186
75929	0.5904	229
75915	0.5075	149
75912	0.2337	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.93	gold quality
jejunal mucosa	UBERON:0000399	96.71	gold quality
colonic mucosa	UBERON:0000317	95.11	gold quality
buccal mucosa cell	CL:0002336	94.77	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.71	gold quality
upper arm skin	UBERON:0004263	92.70	gold quality
left ventricle myocardium	UBERON:0006566	92.02	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.27	gold quality
oocyte	CL:0000023	91.23	gold quality
corpus epididymis	UBERON:0004359	91.07	gold quality
skin of hip	UBERON:0001554	90.07	gold quality
duodenum	UBERON:0002114	89.86	gold quality
kidney epithelium	UBERON:0004819	89.70	gold quality
gingiva	UBERON:0001828	89.58	gold quality
gingival epithelium	UBERON:0001949	89.51	gold quality
upper leg skin	UBERON:0004262	89.38	gold quality
renal medulla	UBERON:0000362	88.74	gold quality
esophagus squamous epithelium	UBERON:0006920	88.48	gold quality
ganglionic eminence	UBERON:0004023	88.08	gold quality
myocardium	UBERON:0002349	87.96	gold quality
liver	UBERON:0002107	87.65	gold quality
cortical plate	UBERON:0005343	87.14	gold quality
lower esophagus mucosa	UBERON:0035834	87.07	gold quality
medial globus pallidus	UBERON:0002477	86.76	gold quality
amniotic fluid	UBERON:0000173	86.59	gold quality
pigmented layer of retina	UBERON:0001782	86.14	gold quality
heart right ventricle	UBERON:0002080	85.74	gold quality
germinal epithelium of ovary	UBERON:0001304	85.69	gold quality
globus pallidus	UBERON:0001875	85.12	gold quality
mucosa of transverse colon	UBERON:0004991	85.02	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	76.09
E-MTAB-9543	yes	25.27
E-HCAD-25	yes	24.11
E-ANND-3	yes	20.89
E-GEOD-93593	yes	6.27
E-GEOD-83139	yes	3.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting NHSL1, 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-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-2682-5P	99.73	67.38	1055

Literature-anchored findings (GeneRIF, showing 2)

• Proteogenomics Integrating Novel Junction Peptide Identification Strategy Discovers Three Novel Protein Isoforms of Human NHSL1 and EEF1B2. (PMID:34420305)
• Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration. (PMID:34584076)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nhsl1b	ENSDARG00000042627
danio_rerio	nhsl1a	ENSDARG00000054537
mus_musculus	Nhsl1	ENSMUSG00000039835
rattus_norvegicus	Nhsl1	ENSRNOG00000060603

Paralogs (3): NHSL3 (ENSG00000162522), NHS (ENSG00000188158), NHSL2 (ENSG00000204131)

Protein

Protein identifiers

NHS-like protein 1 — Q5SYE7 (reviewed: Q5SYE7)

All UniProt accessions (4): E9PAK2, E9PMJ0, Q5SYE7, H0YDF6

UniProt curated annotations — full annotation on UniProt →

Tissue specificity. Widely expressed. Expressed in adult and fetal brain, fetal eyes, adult lens, kidney, liver and intestine.

Similarity. Belongs to the NHS family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5SYE7-1	1	yes
Q5SYE7-2	2

RefSeq proteins (2): NP_001137532, NP_065197 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024845	NHS-like	Family

Pfam: PF15273

UniProt features (47 total): compositionally biased region 21, modified residue 11, region of interest 8, splice variant 2, sequence variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5SYE7-F1	41.89	0.02

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (11): 24, 198, 328, 568, 639, 1089, 1167, 1233, 1386, 1388, 1392

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 89 (showing top): MODULE_418, MARTINEZ_RB1_TARGETS_UP, MODULE_455, GEORGES_TARGETS_OF_MIR192_AND_MIR215, MCBRYAN_PUBERTAL_BREAST_4_5WK_UP, MIKKELSEN_ES_ICP_WITH_H3K4ME3, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A, GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_DN, ZHOU_INFLAMMATORY_RESPONSE_FIMA_DN, E2F1_UP.V1_DN, ESC_J1_UP_EARLY.V1_UP, HAND1_TARGET_GENES, HMG20B_TARGET_GENES, LMTK3_TARGET_GENES, NKX2_2_TARGET_GENES

GO Biological Process (1): cell differentiation (GO:0030154)

GO Molecular Function (0):

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular developmental process	1

Protein interactions and networks

STRING

366 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHSL1	C10orf53	Q8N6V4	398
NHSL1	CCDC150	Q8NCX0	393
NHSL1	CCDC9	Q9Y3X0	389
NHSL1	RALGPS2	Q86X27	367
NHSL1	ECT2L	Q008S8	362
NHSL1	NHSL3	Q9P206	361
NHSL1	TOM1L2	Q6ZVM7	351
NHSL1	VPS26B	Q4G0F5	350
NHSL1	TMEM74B	Q9NUR3	348
NHSL1	CCDC28A	Q8IWP9	345
NHSL1	REPS1	Q96D71	335
NHSL1	ZNF275	Q9NSD4	323
NHSL1	BRK1	Q8WUW1	322
NHSL1	OLFML1	Q6UWY5	321
NHSL1	SPTY2D1	Q68D10	312

IntAct

52 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
NCKAP1	YWHAH	psi-mi:“MI:0914”(association)	0.730
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
PPP2R5A	AXIN1	psi-mi:“MI:0914”(association)	0.530
AMZ1	SUSD5	psi-mi:“MI:0914”(association)	0.530
NHSL3	NCK2	psi-mi:“MI:0914”(association)	0.530
NCKAP1	NHSL1	psi-mi:“MI:0914”(association)	0.530
PPP2R1A	ENSA	psi-mi:“MI:0914”(association)	0.530
GAMMAHV.ORF11	NHSL1	psi-mi:“MI:0915”(physical association)	0.370
Gtf2e2	CASC3	psi-mi:“MI:0914”(association)	0.350
Ndc80	SMCHD1	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
ORF21	USP9Y	psi-mi:“MI:0914”(association)	0.350
Cyfip2	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
ABI1	MYO1C	psi-mi:“MI:0914”(association)	0.350
ABI1	HSPB1	psi-mi:“MI:0914”(association)	0.350
NCKAP1	ENAH	psi-mi:“MI:0914”(association)	0.350
PFN1	WASL	psi-mi:“MI:0914”(association)	0.350
PPP2CA	SUPT5H	psi-mi:“MI:0914”(association)	0.350
WASF1	NHSL1	psi-mi:“MI:0914”(association)	0.350
WASF2	HSBP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (63): NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Proximity Label-MS), NHSL1 (Proximity Label-MS), NHSL1 (Proximity Label-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-RNA), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-MS), NHSL1 (Affinity Capture-RNA)

ESM2 similar proteins: A0FGR0, A0JMD2, A1L253, A3KP40, A7LKB2, A8K5M9, B1AXH1, B1AZP2, B5X7E4, B5XBI1, E2QSX5, F1QPR4, F1QR98, F1RDM5, O14490, O14613, O35413, O54834, O94875, O95886, P0CAX8, P28290, P97836, P97837, P97838, P97839, Q2HJ75, Q3UTJ2, Q3ZBS1, Q5REU9, Q5SYE7, Q60592, Q62417, Q6P0Q8, Q6PD31, Q6PFD5, Q7ZYZ6, Q80Y24, Q8BJ42, Q8BLN6

Diamond homologs: B1AXH1, Q5HYW2, Q5SYE7, Q8CAF4, A2A7S8, Q1LWM5, Q9P206

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	5	81.0×	5e-08
Signaling by GSK3beta mutants	5	81.0×	5e-08
CTNNB1 S33 mutants aren’t phosphorylated	5	81.0×	5e-08
CTNNB1 S37 mutants aren’t phosphorylated	5	81.0×	5e-08
CTNNB1 S45 mutants aren’t phosphorylated	5	81.0×	5e-08
CTNNB1 T41 mutants aren’t phosphorylated	5	81.0×	5e-08
Beta-catenin phosphorylation cascade	5	71.5×	8e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	71.5×	8e-08

GO biological processes:

GO term	Partners	Fold	FDR
Rac protein signal transduction	5	47.6×	1e-05
positive regulation of actin filament polymerization	5	28.0×	8e-05
neuron migration	5	11.3×	3e-03
protein-containing complex assembly	5	9.7×	5e-03
cell migration	9	9.4×	7e-05
intracellular protein localization	5	8.9×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	247
Likely benign	21
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2060 predictions. Top by Δscore:

Variant	Effect	Δscore
6:138441985:AGCT:A	donor_gain	1.0000
6:138441986:G:C	donor_gain	1.0000
6:138447015:G:C	donor_gain	1.0000
6:138447019:C:CT	donor_gain	1.0000
6:138447189:GAACA:G	acceptor_gain	1.0000
6:138447191:ACA:A	acceptor_gain	1.0000
6:138447192:CA:C	acceptor_gain	1.0000
6:138447192:CAC:C	acceptor_gain	1.0000
6:138447194:C:CC	acceptor_gain	1.0000
6:138473300:GCTTA:G	donor_loss	1.0000
6:138473301:CTTAC:C	donor_loss	1.0000
6:138473302:TTA:T	donor_loss	1.0000
6:138473303:TA:T	donor_loss	1.0000
6:138473304:A:AC	donor_gain	1.0000
6:138473304:AC:A	donor_gain	1.0000
6:138473305:C:CA	donor_gain	1.0000
6:138473305:CC:C	donor_gain	1.0000
6:138473305:CCTT:C	donor_gain	1.0000
6:138473445:C:CT	acceptor_gain	1.0000
6:138473447:C:CT	acceptor_gain	1.0000
6:138473450:A:T	acceptor_gain	1.0000
6:138496214:CTTAC:C	donor_loss	1.0000
6:138496215:TTA:T	donor_loss	1.0000
6:138496216:TA:T	donor_loss	1.0000
6:138496217:A:AC	donor_gain	1.0000
6:138496217:AC:A	donor_gain	1.0000
6:138496217:ACC:A	donor_gain	1.0000
6:138496217:ACCCC:A	donor_loss	1.0000
6:138496218:C:CC	donor_gain	1.0000
6:138496218:CC:C	donor_gain	1.0000

AlphaMissense

10446 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:138424634:A:G	L1427P	1.000
6:138424810:T:A	K1368N	1.000
6:138424810:T:G	K1368N	1.000
6:138429717:A:T	I1364N	1.000
6:138424631:A:G	L1428P	0.999
6:138424637:A:G	L1426P	0.999
6:138424645:G:C	F1423L	0.999
6:138424645:G:T	F1423L	0.999
6:138424646:A:G	F1423S	0.999
6:138424647:A:G	F1423L	0.999
6:138424811:T:A	K1368I	0.999
6:138429715:G:C	H1365D	0.999
6:138429717:A:C	I1364S	0.999
6:138429717:A:G	I1364T	0.999
6:138429725:A:C	F1361L	0.999
6:138429725:A:T	F1361L	0.999
6:138429726:A:G	F1361S	0.999
6:138429727:A:G	F1361L	0.999
6:138429729:A:G	L1360P	0.999
6:138496316:C:A	W86C	0.999
6:138496316:C:G	W86C	0.999
6:138496318:A:G	W86R	0.999
6:138496318:A:T	W86R	0.999
6:138424634:A:T	L1427Q	0.998
6:138424642:T:A	K1424N	0.998
6:138424642:T:G	K1424N	0.998
6:138424646:A:C	F1423C	0.998
6:138424807:C:A	R1369S	0.998
6:138424807:C:G	R1369S	0.998
6:138424812:T:C	K1368E	0.998

dbSNP variants (sampled 300 via entrez): RS1000002182 (6:138587354 G>A), RS1000004881 (6:138627860 G>A), RS1000016156 (6:138533836 T>C), RS1000022885 (6:138548339 A>C), RS1000034519 (6:138539497 T>C), RS1000040771 (6:138449788 T>C), RS1000046899 (6:138498133 C>A,T), RS1000051555 (6:138670230 C>A,T), RS1000086249 (6:138648490 T>A), RS1000087972 (6:138626150 T>A), RS1000090122 (6:138541320 T>C), RS1000109007 (6:138668622 T>C), RS1000125108 (6:138586554 A>G), RS1000142954 (6:138670518 T>C), RS1000170595 (6:138603005 A>T)

Disease associations

OMIM: gene MIM:620171 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST008181_2	Spontaneous preterm birth without premature rupture of membranes	2.000000e-06
GCST010702_92	Subcortical volume (MOSTest)	1.000000e-08
GCST010703_286	Brain morphology (MOSTest)	4.000000e-15
GCST011617_26	Cortical surface area	7.000000e-19

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006917	spontaneous preterm birth
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation	3
Cyclosporine	decreases expression, increases expression	3
methylmercuric chloride	affects cotreatment, increases expression	2
perfluorooctanoic acid	increases expression	2
Acetaminophen	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Cadmium Chloride	increases expression	2
FR900359	affects phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
glycidyl methacrylate	increases expression	1
sulforaphane	increases expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	decreases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, increases expression	1

Clinical trials (associated diseases)

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