chr17-43127753-A-G

Position:

• chr17-43127753-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NR_138145.1(NBR2):​n.214+1983A>G variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 151,896 control chromosomes in the GnomAD database, including 8,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.33 (8441 hom., cov: 31)
• Consequence: NBR2 NR_138145.1 intron, non_coding_transcript
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -1.13

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 17-43127753-A-G is Benign according to our data. Variant chr17-43127753-A-G is described in ClinVar as [Benign]. Clinvar id is 209593.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43127753-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBR2	NR_138145.1	n.214+1983A>G		intron_variant, non_coding_transcript_variant
BRCA1	NM_001408458.1	c.-61-11974T>C		intron_variant			NP_001395387.1
NBR2	NR_003108.2	n.214+1983A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBR2	ENST00000657841.1	n.220+1983A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49492 AN: 151778 Hom.: 8435 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.326 AC: 49527 AN: 151896 Hom.: 8441 Cov.: 31 AF XY: 0.331 AC XY: 24596 AN XY: 74210

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.342

Alfa AF: 0.151 Hom.: 317

Bravo AF: 0.312

Asia WGS AF: 0.419 AC: 1457 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

Benign, reviewed by expert panel

curation

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

Jan 12, 2015

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.33 (Asian), 0.21 (African), 0.37 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.99
DANN	Benign	0.16

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34410138; hg19: chr17-41279770;