17-61799256-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_032043.3(BRIP1):c.1184C>A(p.Ala395Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250610Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135418
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461196Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726902
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
This sequence change replaces alanine with aspartic acid at codon 395 of the BRIP1 protein (p.Ala395Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs778992385, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.A395D variant (also known as c.1184C>A), located in coding exon 8 of the BRIP1 gene, results from a C to A substitution at nucleotide position 1184. The alanine at codon 395 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at