chr17-43127865-A-G

Variant names:

• chr17-43127865-A-G
• rs12947782
• ENST00000356906.8:n.351+2095A>G

Variant summary

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

The NM_001408458.1(BRCA1):​c.-61-12086T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 145,184 control chromosomes in the GnomAD database, including 7,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.33 (7923 hom., cov: 28)
• Consequence: BRCA1 NM_001408458.1 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -1.29
• Publications: 8 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):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 17-43127865-A-G is Benign according to our data. Variant chr17-43127865-A-G is described in ClinVar as Benign. ClinVar VariationId is 209595.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001408458.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_001408458.1		c.-61-12086T>C		intron	N/A	NP_001395387.1	B4DES0
	NBR2	NR_003108.2		n.214+2095A>G		intron	N/A
	NBR2	NR_138145.1		n.214+2095A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBR2	ENST00000356906.8	TSL:1	n.351+2095A>G		intron	N/A
	BRCA1	ENST00000634433.2	TSL:5	c.-19-3750T>C		intron	N/A	ENSP00000489431.2	A0A0U1RRA9
	NBR2	ENST00000460115.5	TSL:2	n.161+2095A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.330 AC: 47927 AN: 145106 Hom.: 7917 Cov.: 28

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.330 AC: 47961 AN: 145184 Hom.: 7923 Cov.: 28 AF XY: 0.337 AC XY: 23869 AN XY: 70894

African (AFR) AF: 0.274 AC: 9616 AN: 35122

American (AMR) AF: 0.333 AC: 5043 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1245 AN: 3468

East Asian (EAS) AF: 0.370 AC: 1905 AN: 5144

South Asian (SAS) AF: 0.494 AC: 2354 AN: 4768

European-Finnish (FIN) AF: 0.401 AC: 4201 AN: 10466

Middle Eastern (MID) AF: 0.364 AC: 104 AN: 286

European-Non Finnish (NFE) AF: 0.332 AC: 22527 AN: 67792

Other (OTH) AF: 0.342 AC: 709 AN: 2076

Alfa AF: 0.312 Hom.: 966

Bravo AF: 0.303

Asia WGS AF: 0.420 AC: 1450 AN: 3456

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.20
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs12947782; hg19: chr17-41279882;