rs754929230
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_032043.3(BRIP1):c.1628+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_032043.3 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.1628+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.1628+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251154Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135760
GnomAD4 exome AF: 0.00000754 AC: 11AN: 1458856Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 725852
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1Benign:1
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Jun 11, 2016 | Curator: Arleen D. Auerbach. Submitter to LOVD: Andreas Laner. - |
Uncertain significance, flagged submission | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 03, 2017 | Variant summary: The BRIP1 c.1628+5G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict the weakening of a cannonical splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Benign, flagged submission | clinical testing | GeneDx | Apr 13, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2023 | The c.1628+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the BRIP1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 30, 2021 | This variant causes a G to A nucleotide substitution at the +5 position of intron 11 of the BRIP1 gene. A study using RNA from carrier-derived cells has reported that this variant leads to the skipping of exon 11, creating a premature translation stop signal in the RNA transcript (Leiden Open Variation Database (LOVD) variant number: 0000115868). The aberrant transcript is expected to result in an absent or non-functional protein product. Abnormal RNA splicing resulting from this variant has also been reported in ClinVar (ClinVar variation ID: 461078; communication with an external laboratory). This variant has been reported in individuals affected with ovarian cancer or breast cancer (LOVD; Color internal data). This variant has been identified in 1/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change falls in intron 11 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754929230, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 461078). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 11 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Familial cancer of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
Fanconi anemia complementation group J Uncertain:1
Uncertain significance, flagged submission | clinical testing | Revvity Omics, Revvity | Sep 28, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at