Variant classification summary

NM_032043.3:c.3459T>C

BRIP1 · NP_114432.2:p.(Asp1153=) · NM_032043.3

GRCh37: chr17:59760948 A>G · GRCh38: chr17:61683587 A>G

Gene: BRIP1 Transcript: NM_032043.3

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Asp1153=)

gnomAD AF

0.0006734683246638239 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): 1.62% allele frequency in gnomAD v4.1 Middle Eastern exceeds the >0.3% threshold for benign population frequency.

2

BP4 (Supporting): SpliceAI maximum delta 0.004 is below the 0.1 threshold, indicating no predicted splice impact.

3

Final: Likely Benign by generic ACMG/AMP 2015 combination rules (BS1 Strong + BP4 Supporting).

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong benign criterion plus one supporting benign criterion yields a Likely Benign classification.

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	Not applicable: as a synonymous change (p.Asp1153=) it produces no altered protein, so no null-variant mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no altered amino acid is produced, so there is no change to compare with a known pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with informative parental testing was documented.
PS3	Not assessed	Not assessed: no validated functional assay evidence reporting this variant was identified.
PS4	Not assessed	Not assessed: no case-control data, affected counts, or enrichment statistics for this variant were available.
PM1	N/A	Not applicable: no missense change exists, so mutational hot-spot or critical-domain membership cannot be evaluated.	generic_acmg_combination_rules
PM2	Not met	Not met: the highest relevant population frequency is 1.62% (gnomAD v4.1 Middle Eastern), exceeding the <0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no second pathogenic allele, phasing result, or in-trans evidence was documented.
PM4	N/A	Not applicable: this synonymous variant causes no protein-length change for the criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists to compare against a different pathogenic missense at this residue.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no evidence of presumed de novo occurrence without confirmed parentage was documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or segregation data were documented.
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint properties are irrelevant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta 0.004 does not meet the splice-impact threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype, age-of-onset, or family-history information for the tested individual was supplied.
PP5	Not met	Not met: ClinVar record 136580 has zero expert-panel submissions, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: highest gnomAD v4.1 ancestry frequency is 1.62% (Middle Eastern), below the >5% stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Met	Met (Strong): 1.62% frequency in gnomAD v4.1 Middle Eastern exceeds the >0.3% benign-population threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not assessed	Not assessed: gnomAD reports one homozygote, but aggregate data do not establish a clinically unaffected adult of relevant age.	gnomad_v4 PMID:34012068 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no validated functional assay demonstrating a benign effect for this variant was identified.
BS4	Not assessed	Not assessed: no unaffected tested relatives were documented to evaluate non-segregation.
BP1	N/A	Not applicable: this is a synonymous change, so the criterion for missense variants in a truncating-disease gene does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no data document the variant in cis with a pathogenic allele.
BP3	N/A	Not applicable: no in-frame insertion/deletion or repetitive-region length change is present.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI maximum delta 0.004 is below the 0.1 no-splice-impact threshold.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no phenotype information or alternate molecular diagnosis was available.
BP6	Not met	Not met: ClinVar record 136580 has zero expert-panel submissions, so no expert-panel benign assertion exists.	clinvar
BP7	Not assessed	Not assessed: the no-splice-impact prediction was already counted under BP4, and no conservation evidence was available.	spliceai generic_acmg_combination_rules

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.