# NM_000057.4(BLM):c.3191A>T (p.Asp1064Val)

https://sugi.bio/variant/blm-p-asp1064val

## Summary

**BLM p.Asp1064Val (c.3191A>T)** is classified **Likely pathogenic** in BLM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-23). AlphaMissense: likely pathogenic (0.9338); Absent from gnomAD v4.1; Associated with Bloom syndrome.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs367543032 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BLM gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Bloom syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Neonatal |
| Prevalence | 1-9 / 100 000 (Specific population) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BLM is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Bloom syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Growth delay — Very frequent (99-80%)
- Intrauterine growth retardation — Very frequent (99-80%)
- Small for gestational age — Very frequent (99-80%)
- Abnormality of the immune system — Very frequent (99-80%)
- Decreased circulating antibody level — Very frequent (99-80%)
- Severe postnatal growth retardation — Very frequent (99-80%)
- Adipose tissue loss — Very frequent (99-80%)
- Malar flattening — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000915/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BLM](https://sugi.bio/atlas/gene/BLM/) |
| Protein change (HGVS p.) | p.Asp1064Val |
| Coding change (HGVS c.) | c.3191A>T |
| MANE Select transcript | [NM_000057](https://www.ncbi.nlm.nih.gov/nuccore/NM_000057) |
| dbSNP | [rs367543032](https://www.ncbi.nlm.nih.gov/snp/rs367543032/) |
| Variant type | single nucleotide variant |
| Location | chr15:90794338-90794338 (GRCh38) |
| ClinVar | [VCV3224403](https://www.ncbi.nlm.nih.gov/clinvar/variation/3224403/) |

**All HGVS expressions:** `LRG_20:g.81967A>T`, `LRG_20t1:c.3191A>T`, `NC_000015.10:g.90794338A>T`, `NC_000015.9:g.91337568A>T`, `NG_007272.1:g.81967A>T`, `NM_000057.4:c.3191A>T`, `NM_001287246.2:c.3191A>T`, `NM_001287247.2:c.3191A>T`, `NM_001287248.2:c.2066A>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9338) — concordant with the pathogenic call
- REVEL 0.915 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.279 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.30) — consistent with the pathogenic call
- Conservation: phyloP 9.169, GERP 2.53, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (90,763,155–90,809,165), spanning 46,010 bp. Chi-square p 0.035. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.04**, acceptor gain **0.00**, donor gain **0.30**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.04**, acceptor gain **0.00**, donor gain **0.30**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BLM** population constraint: LOEUF 0.847, pLI 8.7183e-22, missense-Z 1.9677; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **colorectal cancer** — Limited (AD)
- **Bloom syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **1064** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 61.10, 30% of residues very-high.

**16 experimental structure(s)** (PDB): [2KV2](https://www.rcsb.org/structure/2KV2), [2MH9](https://www.rcsb.org/structure/2MH9), [2RRD](https://www.rcsb.org/structure/2RRD), [3WE2](https://www.rcsb.org/structure/3WE2), [3WE3](https://www.rcsb.org/structure/3WE3), [4CDG](https://www.rcsb.org/structure/4CDG).

## What this gene does {#gene-function}

*Describes the biological roles of BLM (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BLM's established molecular role includes four-way junction DNA binding. In Reactome, BLM is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** BLM loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

BLM participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Processive synthesis on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174414) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** four-way junction DNA binding, Y-form DNA binding, bubble DNA binding, p53 binding, DNA binding, DNA helicase activity.

**Biological process:** regulation of cyclin-dependent protein serine/threonine kinase activity, telomere maintenance, double-strand break repair via homologous recombination, DNA double-strand break processing, DNA damage response, mitotic G2 DNA damage checkpoint signaling.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-03-23.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-20 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-23 |

## Associated conditions {#conditions}

[Bloom syndrome](https://sugi.bio/atlas/disease/bloom-syndrome/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Bloom syndrome, Hereditary cancer-predisposing syndrome, Bloom-Torre-Machacek syndrome, Tumor predisposition, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary.

## Similar variants {#similar}

Related BLM variant pages (same residue, condition, or type): [BLM p.Asp1064Gly](/variant/blm-p-asp1064gly), [BLM p.Asp1064Asn](/variant/blm-p-asp1064asn), [BLM p.Asp1064=](/variant/blm-p-asp1064), [BLM c.1087+1G>A](/variant/blm-c-1087-plus-1g-a), [BLM c.1088-1G>A](/variant/blm-c-1088-minus-1g-a), [BLM c.1220+2T>C](/variant/blm-c-1220-plus-2t-c), [BLM c.1220+2T>G](/variant/blm-c-1220-plus-2t-g), [BLM c.1882+2T>C](/variant/blm-c-1882-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3224403). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*