rs3950989

Positions:

• chr17-43085936-G-A
• chr17-43085936-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.4186-3361C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 151,862 control chromosomes in the GnomAD database, including 7,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.32 (7892 hom., cov: 31)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -0.612

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-43085936-G-A is Benign according to our data. Variant chr17-43085936-G-A is described in ClinVar as [Benign]. Clinvar id is 209420.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43085936-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4186-3361C>T		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4186-3361C>T		intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47897 AN: 151744 Hom.: 7886 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.316 AC: 47931 AN: 151862 Hom.: 7892 Cov.: 31 AF XY: 0.322 AC XY: 23910 AN XY: 74208

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.493

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.337

Alfa AF: 0.308 Hom.: 1177

Bravo AF: 0.301

Asia WGS AF: 0.418 AC: 1451 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1

Benign, reviewed by expert panel

curation

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Jan 12, 2015

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3304 (Asian), 0.2154 (African), 0.3562 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.94

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

Other links and lift over

dbSNP: rs3950989; hg19: chr17-41237953;