rs1224034842
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5
The NM_032043.3(BRIP1):c.93+4_93+7del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000377 in 1,592,524 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 splice_donor_5th_base, intron
NM_032043.3 splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.57
Genes affected
BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-61861439-ATACT-A is Pathogenic according to our data. Variant chr17-61861439-ATACT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439032.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=5}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.93+4_93+7del | 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.93+4_93+7del | splice_donor_5th_base_variant, intron_variant | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250976Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135666
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GnomAD4 exome AF: 0.00000139 AC: 2AN: 1440316Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 718010
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74366
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 02, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 16, 2019 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change falls in intron 2 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 is likely to result in the loss of the initiator methionine. This variant is present in population databases (no rsID available, gnomAD 0.008%). 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: 439032). 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 2, and is expected to result in the loss of the initiator methionine (Invitae). Other variant(s) that result in skipping of exon 2 have been determined to be pathogenic (Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2023 | The c.93+4_93+7delAGTA intronic variant, located downstream of coding exon 1 in the BRIP1 gene, results from a deletion of 4 nucleotides at positions c.93+4 to c.93+7. This nucleotide region 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 07, 2016 | - - |
BRIP1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 25, 2023 | The BRIP1 c.93+4_93+7delAGTA variant is predicted to result in an intronic deletion. This variant has been reported in an individual with breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-59938800-ATACT-A). It is interpreted as likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/439032/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2020 | Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 8
Find out detailed SpliceAI scores and Pangolin per-transcript scores at