Classification rationale

BP4 VUS

BRIP1 c.1474-3T>C

The BRIP1 NM_032043.3:c.1474-3T>C (NP_114432.2:p.?) variant has been reported in ClinVar with predominantly benign and likely benign submissions, although uncertain significance submissions are also present.¹ This variant is present in population databases, including gnomAD v4.1 at an overall allele frequency of 0.01185% (191/1611312) and a highest observed South Asian frequency of 0.20440% (186/90996), with similar South Asian enrichment in gnomAD v2.1 at 0.16343% (50/30594); these values are above a 0.1% PM2 rarity threshold but below BA1 and BS1 thresholds.² In silico splice prediction does not support a significant splice effect, with a SpliceAI maximum delta score of 0.11, supporting BP4 and arguing against PP3.³

BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_032043.3 · variants mapped to exon structure

BRIP1 NM_032043.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Computational evidence supports no significant splice effect for this variant. SpliceAI predicts a maximum delta score of 0.11, which is below commonly used thresholds for a meaningful splice impact, and no additional computational result suggested a damaging effect.

SpliceAI max delta score 0.11No REVEL score availableNo BayesDel score available

spliceai ↗

Assessed · not applied · 6 not met · 13 not assessed

Pathogenic

PVS1 BRIP1 loss of function is an established disease mechanism, but this intronic variant is at the -3 position rather than the canonical +/-1,2 splice consensus, and the generic PVS1 framework does not place it in a default null-variant category.

PS1 PS1 applies to a different nucleotide change causing the same amino acid change.

PS2 No confirmed de novo occurrence was identified for this variant, so PS2 is not applied.

PS3 No published functional or RNA study was identified showing a damaging effect of this exact variant on BRIP1 splicing or function, so PS3 is not applied.

PS4 This variant has been reported in ClinVar, but no case-control enrichment or sufficient affected-individual data were identified to show that it is significantly more common in affected individuals than in controls.

PM1 No evidence was identified that this intronic splice-region position lies in a well-established mutational hotspot or a critical region with little benign variation, so PM1 is not met.

PM2 This variant is present in gnomAD and does not meet a rarity threshold for PM2.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context, so PM3 is not applied.

PM6 No assumed de novo occurrence was identified for this variant, so PM6 is not applied.

PP1 No segregation data were identified for this variant, so PP1 is not applied.

PP3 Available computational evidence does not support a deleterious splicing effect.

PP4 No highly specific phenotype or family-history evidence was identified that would support BRIP1-related disease as the sole or highly likely explanation, so PP4 is not applied.

Benign

BA1 This variant does not reach a stand-alone benign frequency threshold.

BS1 This variant does not exceed the benign strong frequency threshold.

BS2 Although this variant is present in population databases, the available data do not establish observation in a context sufficient to show that it is seen in healthy individuals at a level that excludes clinical significance for BRIP1-associated disease.

BS3 No published functional or RNA study was identified demonstrating that this exact variant has no damaging effect on BRIP1 splicing or function, so BS3 is not applied.

BS4 No family data were identified showing lack of segregation of this variant with disease, so BS4 is not applied.

BP2 No data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant, so BP2 is not applied.

BP5 No evidence was identified for an alternative molecular basis that would explain disease independently of this variant, so BP5 is not applied.

N/A · 8 PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000118537; MAF= 0.01185%, 191/1611312 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00204405; MAF= 0.20440%, 186/90996 alleles, homozygotes = 0); grpmax FAF= 0.0018038.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000207267; MAF= 0.02073%, 52/250884 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00163431; MAF= 0.16343%, 50/30594 alleles, homozygotes = 1); grpmax FAF= 0.00127276.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.012% · 191 / 1,611,312
0 hom · FAF 0.18%

South Asian 186 / 90,996	0.2%
Remaining individuals 4 / 62,392	0.0064%
East Asian 1 / 44,780	0.0022%

+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.021% · 52 / 250,884
1 hom · FAF 0.13%

South Asian 50 / 30,594	0.16% 1 hom
Remaining individuals 1 / 6,102	0.016%
European (non-Finnish) 1 / 113,498	0.00088%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (4 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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