# NM_182641.4(BPTF):c.8035GCCCCTCCA[4] (p.2676APP[5])

https://sugi.bio/variant/bptf-p-2676app-5

## Summary

**BPTF p.2676APP[5] (c.8035GCCCCTCCA[4])** is classified **Benign/Likely benign** in BPTF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). Low-frequency (popmax 1.67%, nfe).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs60308484 · 3 submitters · low-frequency (popmax 1.67%, nfe)

## For patients & families {#patients}

This is a change in the BPTF gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BPTF](https://sugi.bio/atlas/gene/BPTF/) |
| Protein change (HGVS p.) | p.2676APP[5] |
| Coding change (HGVS c.) | c.8035GCCCCTCCA[4] |
| MANE Select transcript | [NM_182641](https://www.ncbi.nlm.nih.gov/nuccore/NM_182641) |
| dbSNP | [rs60308484](https://www.ncbi.nlm.nih.gov/snp/rs60308484/) |
| Variant type | Microsatellite |
| Location | chr17:67959642-67959643 (GRCh38) |
| ClinVar | [VCV779282](https://www.ncbi.nlm.nih.gov/clinvar/variation/779282/) |

**All HGVS expressions:** `NC_000017.10:g.65955765GCCCCTCCA[4]`, `NC_000017.11:g.67959649GCCCCTCCA[4]`, `NG_052828.1:g.139133GCCCCTCCA[4]`, `NM_004459.7:c.7984GCCCCTCCA[4]`, `NM_182641.4:c.8035GCCCCTCCA[4]`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -3.667, GERP -1.78 — fast-evolving / accelerated position
- CADD: **PHRED 3.325**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** (CCAGCCCCT). The alignment of this microsatellite is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **1.67%** (nfe) · FAF95 1.65% · FAF99 1.64% · 19,004/1,141,258 in the highest group · 22,120/1,537,940 alleles overall — low-frequency (popmax 1.67%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 2.84% | 35 |
| European (non-Finnish) (grpmax) | 1.67% | 60 |
| Middle Eastern | 1.56% | 64 |
| Remaining individuals (not grpmax-eligible) | 1.44% | 69 |
| Amish (not grpmax-eligible) | 0.989% | 101 |
| Finnish (not grpmax-eligible) | 0.955% | 105 |
| Admixed American | 0.917% | 109 |
| African / African-American | 0.325% | 307 |
| South Asian | 0.129% | 777 |
| East Asian | 0.0158% | 6,347 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**BPTF** population constraint: LOEUF 0.09, pLI 1, missense-Z 5.0945; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}


**46 experimental structure(s)** (PDB): [2F6J](https://www.rcsb.org/structure/2F6J), [2F6N](https://www.rcsb.org/structure/2F6N), [2FSA](https://www.rcsb.org/structure/2FSA), [2FUI](https://www.rcsb.org/structure/2FUI), [2FUU](https://www.rcsb.org/structure/2FUU), [2RI7](https://www.rcsb.org/structure/2RI7) — incl. mutant structure 2RI7.

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

*Describes the biological roles of BPTF (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:** BPTF's established molecular role includes sequence-specific DNA binding.


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

**Molecular function:** sequence-specific DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, brain development, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related BPTF variant pages (same residue, condition, or type): [BPTF p.Thr783fs](/variant/bptf-p-thr783fs), [BPTF p.Asp184_Asp185dup](/variant/bptf-p-asp184-asp185dup), [BPTF p.Glu874del](/variant/bptf-p-glu874del), [BPTF p.2676APP[4]](/variant/bptf-p-2676app-4), [BPTF p.2676APP[6]](/variant/bptf-p-2676app-6), [BPTF p.Glu148del](/variant/bptf-p-glu148del), [BPTF p.Glu163del](/variant/bptf-p-glu163del), [BPTF p.Pro80_Pro82del](/variant/bptf-p-pro80-pro82del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 779282). 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.*