17-43125295-G-C

Variant names:

• chr17-43125295-G-C
• rs1262271602
• ENST00000354071.8:n.21C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000354071.8(BRCA1):​n.21C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000329 in 303,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: BRCA1 ENST00000354071.8 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000354071.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.-44C>G		5_prime_UTR	Exon 1 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.-44C>G		5_prime_UTR	Exon 1 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.-133C>G		5_prime_UTR	Exon 1 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000354071.8	TSL:1	n.21C>G		non_coding_transcript_exon	Exon 1 of 10
	BRCA1	ENST00000492859.5	TSL:1	n.-44C>G		non_coding_transcript_exon	Exon 1 of 11	ENSP00000420253.1
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.-44C>G		5_prime_UTR	Exon 1 of 23	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000765 AC: 1 AN: 130746 AF XY: 0.0000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000329 AC: 1 AN: 303938 Hom.: 0 Cov.: 0 AF XY: 0.00000578 AC XY: 1 AN XY: 173066

African (AFR) AF: 0.00 AC: 0 AN: 8628

American (AMR) AF: 0.00 AC: 0 AN: 27280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10790

East Asian (EAS) AF: 0.00 AC: 0 AN: 9204

South Asian (SAS) AF: 0.00 AC: 0 AN: 59740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2778

European-Non Finnish (NFE) AF: 0.00000629 AC: 1 AN: 158920

Other (OTH) AF: 0.00 AC: 0 AN: 14230

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.38
PhyloP100		0.33
PromoterAI		-0.20	Neutral

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

Other links and lift over

dbSNP: rs1262271602; hg19: chr17-41277312;