17-43125979-T-C

Variant names:

• chr17-43125979-T-C
• rs3092986
• ENST00000356906.8:n.351+209T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000356906.8(NBR2):​n.351+209T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 137,476 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.050 (208 hom., cov: 32)
• Consequence: NBR2 ENST00000356906.8 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 1.08
• Publications: 10 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-43125979-T-C is Benign according to our data. Variant chr17-43125979-T-C is described in ClinVar as Benign. ClinVar VariationId is 209581.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0699 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356906.8. 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_001408458.1		c.-61-10200A>G		intron	N/A	NP_001395387.1
	NBR2	NR_003108.2		n.214+209T>C		intron	N/A
	NBR2	NR_138145.1		n.214+209T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBR2	ENST00000356906.8	TSL:1	n.351+209T>C		intron	N/A
	BRCA1	ENST00000634433.2	TSL:5	c.-19-1864A>G		intron	N/A	ENSP00000489431.2
	NBR2	ENST00000460115.5	TSL:2	n.161+209T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 6828 AN: 137362 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.0180

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.000663

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.0600

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

GnomAD4 genome AF: 0.0497 AC: 6829 AN: 137476 Hom.: 208 Cov.: 32 AF XY: 0.0495 AC XY: 3305 AN XY: 66744

African (AFR) AF: 0.0124 AC: 486 AN: 39282

American (AMR) AF: 0.0427 AC: 584 AN: 13678

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 280 AN: 3126

East Asian (EAS) AF: 0.000663 AC: 3 AN: 4524

South Asian (SAS) AF: 0.0169 AC: 61 AN: 3606

European-Finnish (FIN) AF: 0.0981 AC: 879 AN: 8962

Middle Eastern (MID) AF: 0.0530 AC: 14 AN: 264

European-Non Finnish (NFE) AF: 0.0717 AC: 4395 AN: 61318

Other (OTH) AF: 0.0594 AC: 112 AN: 1884

Alfa AF: 0.0597 Hom.: 34

Bravo AF: 0.0406

Asia WGS AF: 0.00550 AC: 19 AN: 3470

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 0.06 (European), derived from 1000 genomes (2012-04-30).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.51
PhyloP100		1.1
PromoterAI		0.052	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3092986; hg19: chr17-41277996;