# NM_019616.4(F7):c.867_868insCA (p.Val290fs)

https://sugi.bio/variant/f7-p-val290fs

## Summary

**F7 p.Val290fs (c.867_868insCA)** is classified **Uncertain significance** in F7 (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with congenital factor VII deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2503054471 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the F7 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to congenital factor VII deficiency.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | F7 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Congenital factor VII deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intracranial hemorrhage — Very frequent (99-80%)
- Gastrointestinal hemorrhage — Very frequent (99-80%)
- Menorrhagia — Frequent (79-30%)
- Gingival bleeding — Frequent (79-30%)
- Epistaxis — Frequent (79-30%)
- Bruising susceptibility — Frequent (79-30%)
- Prolonged bleeding after surgery — Frequent (79-30%)
- Joint hemorrhage — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002238/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F7](https://sugi.bio/atlas/gene/F7/) |
| Protein change (HGVS p.) | p.Val290fs |
| Coding change (HGVS c.) | c.867_868insCA |
| MANE Select transcript | [NM_019616](https://www.ncbi.nlm.nih.gov/nuccore/NM_019616) |
| dbSNP | [rs2503054471](https://www.ncbi.nlm.nih.gov/snp/rs2503054471/) |
| Variant type | Insertion |
| Location | chr13:113118540-113118541 (GRCh38) |
| ClinVar | [VCV2584870](https://www.ncbi.nlm.nih.gov/clinvar/variation/2584870/) |

**All HGVS expressions:** `LRG_548:g.742_743insCA`, `LRG_554:g.17750_17751insCA`, `LRG_554t1:c.933_934insCA`, `LRG_554t2:c.867_868insCA`, `NC_000013.10:g.113772854_113772855insCA`, `NC_000013.11:g.113118540_113118541insCA`, `NG_009258.1:g.742_743insCA`, `NG_009262.1:g.17750_17751insCA`, `NM_000131.5:c.933_934insCA`, `NM_001267554.2:c.681_682insCA`, `NM_019616.4:c.867_868insCA`, `NR_051961.2:n.951_952insCA`

## 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 -20, GERP -3.4 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.113, pLI 1.1139e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (8 of 8)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**F7** population constraint: LOEUF 1.113, pLI 1.1139e-11, missense-Z 0.3692; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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):

- **factor VII deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **290** lies in a β-strand; a disulfide bond; the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 82.64, 49% of residues very-high.

**114 experimental structure(s)** (PDB): [1BF9](https://www.rcsb.org/structure/1BF9), [1CVW](https://www.rcsb.org/structure/1CVW), [1DAN](https://www.rcsb.org/structure/1DAN), [1DVA](https://www.rcsb.org/structure/1DVA), [1F7E](https://www.rcsb.org/structure/1F7E), [1F7M](https://www.rcsb.org/structure/1F7M) — incl. mutant structure 1FAK.

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

*Describes the biological roles of F7 (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.*


### Pathways affected {#pathways}

F7 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Gamma-carboxylation of protein precursors](https://reactome.org/content/detail/R-HSA-159740) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Removal of aminoterminal propeptides from gamma-carboxylated proteins](https://reactome.org/content/detail/R-HSA-159782) | curated |
| [Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus](https://reactome.org/content/detail/R-HSA-159763) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140834) | other |
| [BMAL1:CLOCK,NPAS2 activates circadian expression](https://reactome.org/content/detail/R-HSA-1368108) | electronic |

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

**Biological process:** positive regulation of leukocyte chemotaxis, blood coagulation, positive regulation of platelet-derived growth factor receptor signaling pathway, protein processing, positive regulation of TOR signaling, positive regulation of positive chemotaxis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Uncertain significance | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[congenital factor VII deficiency](https://sugi.bio/atlas/disease/congenital-factor-vii-deficiency/).

**Reported phenotype names (ClinVar):** Congenital factor VII deficiency.

## Same-residue context {#hotspot}

Residue **290** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [F7 p.Val290Met](/variant/f7-p-val290met). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related F7 variant pages (same residue, condition, or type): [F7 p.Val290Met](/variant/f7-p-val290met), [F7 p.Val290Leu](/variant/f7-p-val290leu), [F7 c.225+1G>C](/variant/f7-c-225-plus-1g-c), [F7 c.364+1G>A](/variant/f7-c-364-plus-1g-a), [F7 c.505+78G>A](/variant/f7-c-505-plus-78g-a), [F7 c.615+1G>T](/variant/f7-c-615-plus-1g-t), [F7 c.739+1G>A](/variant/f7-c-739-plus-1g-a), [F7 c.-30A>C](/variant/f7-c-minus-30a-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 2584870). 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.*