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rs1224034842

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 6.57
Variant links:
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
BRIP1NM_032043.3 linkuse as main transcriptc.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
BRIP1ENST00000259008.7 linkuse as main transcriptc.93+4_93+7del splice_donor_5th_base_variant, intron_variant 1 NM_032043.3 P2Q9BX63-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250976
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135666
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000139
AC:
2
AN:
1440316
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
718010
show subpopulations
Gnomad4 AFR exome
AF:
0.0000303
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.15e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000113

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 submitterclinical testingBaylor GeneticsFeb 02, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterDec 16, 2019- -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeJan 10, 2024This 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 submitterclinical testingAmbry GeneticsAug 24, 2023The 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 submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 07, 2016- -
BRIP1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 25, 2023The 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 submitterclinical testingMendelicsJul 02, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 10, 2020Intronic +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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.94
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.94
Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1224034842; hg19: chr17-59938800; API