17-43071137-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_007294.4(BRCA1):​c.4777A>T​(p.Ile1593Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

1
3
15

Clinical Significance

Likely benign no assertion criteria provided B:1O:1

Conservation

PhyloP100: -1.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12551612).
BP6
Variant 17-43071137-T-A is Benign according to our data. Variant chr17-43071137-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 55286.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.4777A>T p.Ile1593Leu missense_variant 15/23 ENST00000357654.9 NP_009225.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.4777A>T p.Ile1593Leu missense_variant 15/231 NM_007294.4 ENSP00000350283 P4P38398-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Medical and Surgical Sciences, University of BolognaSep 01, 2023PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Familial cancer of breast Other:1
not provided, no classification providedliterature onlyClinVar Staff, National Center for Biotechnology Information (NCBI)-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
0.053
DANN
Benign
0.56
DEOGEN2
Benign
0.078
.;T;.;.;T;.;.;.;T;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.69
T;T;T;T;T;T;T;T;T;T
M_CAP
Uncertain
0.098
D
MetaRNN
Benign
0.13
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
1.1
.;L;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.21
N;N;.;N;.;N;N;N;N;N
REVEL
Uncertain
0.55
Sift
Benign
0.42
T;T;.;T;.;T;T;T;T;T
Sift4G
Benign
0.76
T;T;T;T;T;T;T;.;.;T
Polyphen
0.025, 0.0
.;B;.;.;.;.;.;.;B;.
Vest4
0.71
MVP
0.21
MPC
0.082
ClinPred
0.063
T
GERP RS
-2.9
Varity_R
0.034
gMVP
0.11

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: rs397509197; hg19: chr17-41223154; API