17-43067324-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007294.4(BRCA1):​c.5074+284C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 282,550 control chromosomes in the GnomAD database, including 11,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.24 ( 4355 hom., cov: 24)
Exomes 𝑓: 0.30 ( 7022 hom. )

Consequence

BRCA1
NM_007294.4 intron

Scores

2

Clinical Significance

Benign reviewed by expert panel B:3O:1

Conservation

PhyloP100: 0.548
Variant links:
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
Variant 17-43067324-G-T is Benign according to our data. Variant chr17-43067324-G-T is described in ClinVar as [Benign]. Clinvar id is 127127.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067324-G-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkc.5074+284C>A intron_variant ENST00000357654.9 NP_009225.1 P38398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkc.5074+284C>A intron_variant 1 NM_007294.4 ENSP00000350283.3 P38398-1

Frequencies

GnomAD3 genomes
AF:
0.238
AC:
34470
AN:
144560
Hom.:
4347
Cov.:
24
show subpopulations
Gnomad AFR
AF:
0.158
Gnomad AMI
AF:
0.239
Gnomad AMR
AF:
0.264
Gnomad ASJ
AF:
0.264
Gnomad EAS
AF:
0.188
Gnomad SAS
AF:
0.431
Gnomad FIN
AF:
0.330
Gnomad MID
AF:
0.285
Gnomad NFE
AF:
0.255
Gnomad OTH
AF:
0.251
GnomAD4 exome
AF:
0.298
AC:
41158
AN:
137920
Hom.:
7022
Cov.:
0
AF XY:
0.316
AC XY:
23749
AN XY:
75042
show subpopulations
Gnomad4 AFR exome
AF:
0.170
Gnomad4 AMR exome
AF:
0.274
Gnomad4 ASJ exome
AF:
0.249
Gnomad4 EAS exome
AF:
0.187
Gnomad4 SAS exome
AF:
0.475
Gnomad4 FIN exome
AF:
0.326
Gnomad4 NFE exome
AF:
0.263
Gnomad4 OTH exome
AF:
0.257
GnomAD4 genome
AF:
0.238
AC:
34485
AN:
144630
Hom.:
4355
Cov.:
24
AF XY:
0.245
AC XY:
17131
AN XY:
69828
show subpopulations
Gnomad4 AFR
AF:
0.158
Gnomad4 AMR
AF:
0.264
Gnomad4 ASJ
AF:
0.264
Gnomad4 EAS
AF:
0.188
Gnomad4 SAS
AF:
0.431
Gnomad4 FIN
AF:
0.330
Gnomad4 NFE
AF:
0.255
Gnomad4 OTH
AF:
0.255
Alfa
AF:
0.235
Hom.:
555
Bravo
AF:
0.217
Asia WGS
AF:
0.287
AC:
998
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:3Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJun 23, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Jan 12, 2015Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.1626 (Asian), 0.1138 (African), 0.2704 (European), derived from 1000 genomes (2012-04-30). -
Familial cancer of breast Other:1
not provided, no classification providedliterature onlyGenomic Research Center, Shahid Beheshti University of Medical Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
CADD
Benign
3.0
DANN
Benign
0.74
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs11654396; hg19: chr17-41219341; API