17-43127866-GAC-G

Variant names:

• chr17-43127866-GAC-G
• rs112881775
• ENST00000356906.7:n.131+2097_131+2098delAC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001408458.1(BRCA1):​c.-61-12089_-61-12088delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 151,448 control chromosomes in the GnomAD database, including 2,600 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.11 (2600 hom., cov: 26)
• Consequence: BRCA1 NM_001408458.1 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.153

Genes affected

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]

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 -16 ACMG points.

• BP6: Variant 17-43127866-GAC-G is Benign according to our data. Variant chr17-43127866-GAC-G is described in ClinVar as [Benign]. Clinvar id is 209596.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43127866-GAC-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_001408458.1	c.-61-12089_-61-12088delGT		intron_variant	Intron 1 of 21		NP_001395387.1
NBR2	NR_003108.2	n.214+2098_214+2099delCA		intron_variant	Intron 1 of 4
NBR2	NR_138145.1	n.214+2098_214+2099delCA		intron_variant	Intron 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBR2	ENST00000356906.7	n.131+2097_131+2098delAC		intron_variant	Intron 1 of 3	1
BRCA1	ENST00000634433.2	c.-19-3753_-19-3752delGT		intron_variant	Intron 1 of 20	5		ENSP00000489431.2
NBR2	ENST00000460115.5	n.161+2097_161+2098delAC		intron_variant	Intron 1 of 4	2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15890 AN: 151332 Hom.: 2580 Cov.: 26

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0378

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.00884

Gnomad OTH AF: 0.0743

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

GnomAD4 genome AF: 0.105 AC: 15953 AN: 151448 Hom.: 2600 Cov.: 26 AF XY: 0.102 AC XY: 7532 AN XY: 74012

Gnomad4 AFR AF: 0.351

Gnomad4 AMR AF: 0.0377

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.00152

Gnomad4 NFE AF: 0.00884

Gnomad4 OTH AF: 0.0735

Alfa AF: 0.0653 Hom.: 197

Bravo AF: 0.120

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Jan 12, 2015

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.37 (African), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs112881775; hg19: chr17-41279883;