ENST00000634433.2:c.-19-20494A>T

Variant names:

• chr17-43144609-T-A
• rs1546585
• ENST00000634433.2:c.-19-20494A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000634433.2(BRCA1):​c.-19-20494A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 166,114 control chromosomes in the GnomAD database, including 2,668 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.11 (2661 hom., cov: 32)
  • Exomes 𝑓: 0.011 (7 hom.)
• Consequence: BRCA1 ENST00000634433.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385
• Publications: 4 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000634433.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_001408458.1		c.-62+25517A>T		intron	N/A	NP_001395387.1	B4DES0
	NBR2	NR_003108.2		n.1012-119T>A		intron	N/A
	NBR2	NR_138145.1		n.1175+2033T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000634433.2	TSL:5	c.-19-20494A>T		intron	N/A	ENSP00000489431.2	A0A0U1RRA9
	NBR2	ENST00000460115.5	TSL:2	n.959-119T>A		intron	N/A
	NBR2	ENST00000467245.5	TSL:2	n.1088+2033T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16107 AN: 152136 Hom.: 2641 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.0750

GnomAD4 exome AF: 0.0107 AC: 148 AN: 13860 Hom.: 7 AF XY: 0.0122 AC XY: 91 AN XY: 7458

African (AFR) AF: 0.304 AC: 17 AN: 56

American (AMR) AF: 0.0204 AC: 32 AN: 1566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 102

East Asian (EAS) AF: 0.00 AC: 0 AN: 316

South Asian (SAS) AF: 0.0254 AC: 43 AN: 1692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2426

Middle Eastern (MID) AF: 0.0500 AC: 1 AN: 20

European-Non Finnish (NFE) AF: 0.00588 AC: 42 AN: 7138

Other (OTH) AF: 0.0239 AC: 13 AN: 544

GnomAD4 genome AF: 0.106 AC: 16170 AN: 152254 Hom.: 2661 Cov.: 32 AF XY: 0.103 AC XY: 7656 AN XY: 74458

African (AFR) AF: 0.353 AC: 14641 AN: 41486

American (AMR) AF: 0.0378 AC: 579 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4830

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10624

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.00885 AC: 602 AN: 68034

Other (OTH) AF: 0.0742 AC: 157 AN: 2116

Alfa AF: 0.0661 Hom.: 203

Bravo AF: 0.120

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.8
DANN	Benign	0.78
PhyloP100		-0.39

Splicing

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

Other links and lift over

dbSNP: rs1546585; hg19: chr17-41296626;