Variant classification summary

NM_032043.3:c.1474-3T>C

BRIP1 · NP_114432.2:p.? · NM_032043.3

GRCh37: chr17:59861788 A>G · GRCh38: chr17:61784427 A>G

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

BP4 supporting

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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. No RNA evidence was identified to show that this variant causes an abnormal transcript, so PVS1 is not applied.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	PS1 applies to a different nucleotide change causing the same amino acid change. This intronic variant has no established protein consequence, and no same-protein-change comparison was identified.
PS2	Not assessed	No confirmed de novo occurrence was identified for this variant, so PS2 is not applied.	clinvar
PS3	Not assessed	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.	clinvar
PS4	Not assessed	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. PS4 is not applied.	clinvar
PM1	Not met	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	Not met	This variant is present in gnomAD and does not meet a rarity threshold for PM2. In gnomAD v4.1, the highest observed population frequency is 0.20440% in South Asian individuals, which is above the 0.1% PM2 threshold; gnomAD v2.1 also shows a South Asian frequency of 0.16343%, above the same threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	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.
PM4	N/A	PM4 applies to protein length changes such as in-frame insertions/deletions or stop-loss variants. This is an intronic splice-region variant with no established protein length change.
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is intronic and does not have an established missense consequence.
PM6	Not assessed	No assumed de novo occurrence was identified for this variant, so PM6 is not applied.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 is not applied.	clinvar
PP2	N/A	PP2 is a missense criterion and is not applicable to this intronic splice-region variant.
PP3	Not met	Available computational evidence does not support a deleterious splicing effect. SpliceAI shows a maximum delta score of 0.11, which is below commonly used concern thresholds, and no REVEL, BayesDel, or HCI prior result was available for this intronic variant.	spliceai
PP4	Not assessed	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.
PP5	N/A	PP5 was not applied because reputable-source assertions without independently reviewable primary evidence were not used as stand-alone pathogenic evidence.
BA1	Not met	This variant does not reach a stand-alone benign frequency threshold. The highest observed population frequency is 0.20440% in gnomAD v4.1 South Asian individuals, which is below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	This variant does not exceed the benign strong frequency threshold. The highest observed population frequency is 0.20440% in gnomAD v4.1 South Asian individuals, which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	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. BS2 is not applied.	gnomad_v2 gnomad_v4
BS3	Not assessed	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.	clinvar
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with disease, so BS4 is not applied.	clinvar
BP1	N/A	BP1 is a missense criterion and is not applicable to this intronic splice-region variant.
BP2	Not assessed	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.
BP3	N/A	BP3 applies to in-frame variants in repetitive regions without known function and is not applicable to this intronic splice-region variant.
BP4	Met	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
BP5	Not assessed	No evidence was identified for an alternative molecular basis that would explain disease independently of this variant, so BP5 is not applied.
BP6	N/A	BP6 was not applied because reputable-source assertions without independently reviewable primary evidence were not used as stand-alone benign evidence.
BP7	N/A	BP7 is not applicable because this is not a synonymous variant, and it lies close to the splice acceptor rather than representing a silent coding change with no expected splice impact.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.