rs993065651

Variant names:

• chr17-43125417-T-A
• rs993065651
• ENST00000471181.7:c.-166A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000471181.7(BRCA1):​c.-166A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 378,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: BRCA1 ENST00000471181.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.18
• Publications: 1 publications found

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]

NBR2 (HGNC:20691): (neighbor of BRCA1 lncRNA 2) This gene was identified by its close proximity on chromosome 17 to tumor suppressor gene BRCA1. Experimental evidence indicates that the two genes share a bi-directional promoter. Transcription for either gene is controlled individually by distinct transcriptional repressor factors. A short (112 amino acid) open reading frame is observed which includes a region derived from a LINE1 element. A strong Kozak signal is not observed for the putative ORF and the stop codon is more than 55 nucleotides upstream of the last splice site for the transcript, suggesting that the transcript is subject to nonsense-mediated decay. Therefore, this gene does not appear to encode a protein. Glucose starvation induces the expression of this gene and the long non-coding RNA transcribed by it functions with AMP-activated protein kinase in mediating the energy stress response. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.-166A>T		upstream_gene_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.-166A>T		upstream_gene_variant		1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 32

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

GnomAD4 exome AF: 0.00000443 AC: 1 AN: 225910 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000166 AC: 1 AN: 6042

American (AMR) AF: 0.00 AC: 0 AN: 16352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6156

East Asian (EAS) AF: 0.00 AC: 0 AN: 8326

South Asian (SAS) AF: 0.00 AC: 0 AN: 48322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 824

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 119508

Other (OTH) AF: 0.00 AC: 0 AN: 10640

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

African (AFR) AF: 0.0000965 AC: 4 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.1
DANN	Benign	0.88
PhyloP100		-1.2
PromoterAI		0.15	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: 2

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

Other links and lift over

dbSNP: rs993065651; hg19: chr17-41277434;