NM_032043.3:c.1794+19T>C

BRIP1 · NP_114432.2:p.? · NM_032043.3

GRCh37: chr17:59858182 A>G · GRCh38: chr17:61780821 A>G

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.?

gnomAD AF

2.8529042565331506e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_032043.3:c.1794+19T>C is a deep intronic substitution in BRIP1 intron 12 with no predicted effect on splicing (SpliceAI max delta = 0.10).

The variant is extremely rare in population databases (gnomAD v2.1 AF = 0.00389%, v4.1 AF = 0.00285%), meeting PM2 at supporting level.

Multiple lines of computational evidence predict no deleterious splicing effect, meeting BP4 at supporting benign level.

ClinVar reports Likely benign classification by 3 clinical laboratories (GeneDx, Color Health, Labcorp/Invitae), though the 1-star review status does not independently meet BP6 at supporting level under current PP5/BP6 guidance.

No functional studies, case-control data, cosegregation data, de novo reports, or variant-specific literature exist for this variant.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient to classify as either Likely Pathogenic or Likely Benign. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.

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	N/A	NM_032043.3:c.1794+19T>C is a deep intronic substitution (intron 12, +19 position) that does not fall into the ClinGen PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). SpliceAI max delta score of 0.10 confirms no predicted splicing impact. PVS1 is not applicable to this variant class.	pvs1_generic_framework spliceai
PS1	N/A	This is an intronic variant with no amino acid change. PS1 requires the same amino acid change as an established pathogenic variant and is not applicable to non-coding variants.
PS2	Not met	No de novo evidence is available for NM_032043.3:c.1794+19T>C. No publications report de novo occurrence of this variant, and no de novo data are present in ClinVar submissions.
PS3	Not met	No functional studies have been performed on NM_032043.3:c.1794+19T>C. No experimental data exist for this specific variant or for a systematically characterized range that includes this intronic position. Domain-level or gene-level functional characterization does not satisfy PS3 requirements.
PS4	Not met	No case-control or case series data are available for NM_032043.3:c.1794+19T>C. The papers flagged for PS4 evaluation (PMID:18163131, PMID:24366376, PMID:24366402, PMID:31429903, PMID:35802134) are general guidelines and review articles that do not report variant-specific case observations.
PS5	Not met	No reputable source has classified NM_032043.3:c.1794+19T>C as pathogenic. The ClinVar classification is Likely benign (ClinVar Variation ID 377594), and no source asserts pathogenicity.	clinvar
PM1	N/A	This is a deep intronic variant (c.1794+19T>C) that does not alter protein sequence. PM1 requires location in a mutational hotspot or critical functional domain at the protein level. An intronic variant outside splice consensus regions does not qualify.
PM2	Met	NM_032043.3:c.1794+19T>C is present at extremely low frequency in gnomAD (v2.1 AF = 0.00389%, 11/282,822 alleles; v4.1 AF = 0.00285%, 46/1,612,392 alleles), well below the 0.1% PM2 threshold. The variant is absent from most subpopulations, has 0 homozygotes, and has a grpmax FAF of 1.122e-05. Observed primarily in the Ashkenazi Jewish population (ASJ AF = 0.058%) but remains rare even in this subpopulation.	gnomad_v2 gnomad_v4
PM5	N/A	NM_032043.3:c.1794+19T>C is an intronic variant with no amino acid change (NP_114432.2:p.?). PM5 requires a different missense change at the same codon as an established pathogenic variant, which cannot be assessed for a non-coding intronic variant.	pm5_candidates
PM6	Not met	No de novo evidence is available for NM_032043.3:c.1794+19T>C. No publications or database entries report de novo occurrence of this variant with confirmed maternity and paternity.
PP1	Not assessed	No cosegregation data are available for NM_032043.3:c.1794+19T>C. No family studies or pedigrees have been reported in the literature or databases.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_032043.3:c.1794+19T>C is an intronic variant, not a missense change, and therefore PP2 does not apply.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI max delta score is 0.10, indicating no predicted splicing impact. REVEL and BayesDel scores are not available for this intronic variant (not applicable to non-coding changes). HCI prior probability is not supported for BRIP1. No in silico evidence supports pathogenicity.	spliceai
PP4	Not met	No patient phenotype or clinical data are available to evaluate whether the proband's presentation is specific for BRIP1-related disease. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classification for NM_032043.3:c.1794+19T>C is Likely benign (Variation ID 377594), not pathogenic. Additionally, the review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for PP5 application. No reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	NM_032043.3:c.1794+19T>C has a gnomAD v2.1 total allele frequency of 0.00389% (3.89e-05), which is far below the 1% BA1 threshold for a benign standing variant. The variant is too rare to meet BA1.	gnomad_v2 gnomad_v4
BS1	Not met	NM_032043.3:c.1794+19T>C has a gnomAD v2.1 total allele frequency of 0.00389%, which is below the 0.3% BS1 threshold under generic ACMG rules. The variant frequency does not exceed the expected prevalence for BRIP1-associated disorders.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence that NM_032043.3:c.1794+19T>C has been observed in a healthy adult individual as homozygous or in trans with a known pathogenic BRIP1 variant. gnomAD reports 0 homozygotes across both v2.1 and v4.1. BS2 requires specific observation in a healthy control context.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect have been performed for NM_032043.3:c.1794+19T>C. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.
BS4	Not assessed	No cosegregation data are available for NM_032043.3:c.1794+19T>C. BS4 requires lack of cosegregation with disease in affected family members, which cannot be evaluated without family studies.
BP1	N/A	BP1 applies specifically to missense variants in genes where truncating variants are a predominant disease mechanism. NM_032043.3:c.1794+19T>C is an intronic variant, not a missense change, and BP1 does not apply.
BP2	Not assessed	No data are available on whether NM_032043.3:c.1794+19T>C has been observed in trans with a known pathogenic BRIP1 variant. BP2 requires specific observation in trans in an individual without disease features.
BP3	N/A	Skipped per instructions: this variant is a substitution, not an in-frame indel in a repetitive region.
PM3	N/A	Skipped per instructions: no data on phase-confirmed trans configuration with a pathogenic variant; PM3 is only applicable when both alleles carry pathogenic variants.
PM4	N/A	Skipped per instructions: this variant is a substitution, not a non-frameshift indel or stop-loss variant causing protein length change.
BP4	Met	Multiple lines of computational evidence support a benign interpretation. SpliceAI predicts no significant splicing impact for NM_032043.3:c.1794+19T>C (max delta score = 0.10). The variant is located at intron position +19, well outside the canonical splice donor/acceptor consensus. No in silico tool predicts a deleterious effect on splicing.	spliceai
BP5	Not assessed	No information is available regarding an alternate molecular basis for disease in the proband. BP5 requires a pathogenic variant in an alternative gene that explains the patient's phenotype.
BP6	Not met	Three clinical laboratories (GeneDx, Color Health, Labcorp/Invitae) independently classify NM_032043.3:c.1794+19T>C as Likely benign in ClinVar (Variation ID 377594). However, the aggregate ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for BP6 application at supporting level under current PP5/BP6 guidance. The available submissions are concordant for a benign interpretation but lack expert panel review.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_032043.3:c.1794+19T>C is an intronic variant, not a synonymous coding change. BP7 does not apply to intronic substitutions.

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