17-43125376-G-C

Variant names:

• chr17-43125376-G-C
• rs148196794
• ENST00000471181.7:c.-125C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000471181.7(BRCA1):​c.-125C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000772 in 259,102 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: 0.0000077 (0 hom.)
• Consequence: BRCA1 ENST00000471181.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000471181.7. 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_001408458.1		c.-61-9597C>G		intron	N/A	NP_001395387.1
	BRCA1	NM_007294.4	MANE Select	c.-125C>G		upstream_gene	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.-125C>G		upstream_gene	N/A	NP_001394510.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000471181.7	TSL:1	c.-125C>G		5_prime_UTR	Exon 1 of 24	ENSP00000418960.2
	BRCA1	ENST00000494123.6	TSL:1	c.-119C>G		5_prime_UTR	Exon 1 of 23	ENSP00000419103.2
	BRCA1	ENST00000468300.5	TSL:1	c.-119C>G		5_prime_UTR	Exon 1 of 22	ENSP00000417148.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000772 AC: 2 AN: 259102 Hom.: 0 Cov.: 0 AF XY: 0.00000687 AC XY: 1 AN XY: 145506

African (AFR) AF: 0.00 AC: 0 AN: 6734

American (AMR) AF: 0.00 AC: 0 AN: 20416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8738

East Asian (EAS) AF: 0.00 AC: 0 AN: 8380

South Asian (SAS) AF: 0.00 AC: 0 AN: 55780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1822

European-Non Finnish (NFE) AF: 0.0000150 AC: 2 AN: 133608

Other (OTH) AF: 0.00 AC: 0 AN: 12018

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.83
PhyloP100		1.2
PromoterAI		-0.12	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: rs148196794; hg19: chr17-41277393;