ENST00000618469.2:c.-453C>G

Variant names:

• chr17-43125170-G-C
• rs799905
• ENST00000618469.2:c.-453C>G

Variant summary

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

The ENST00000618469.2(BRCA1):​c.-453C>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 0.434 in 443,588 control chromosomes in the GnomAD database, including 46,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20395 hom., cov: 22)
  • Exomes 𝑓: 0.40 (26073 hom.)
• Consequence: BRCA1 ENST00000618469.2 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -2.23
• Publications: 26 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-43125170-G-C is Benign according to our data. Variant chr17-43125170-G-C is described in ClinVar as [Benign]. Clinvar id is 189123.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.-20+101C>G		intron_variant	Intron 1 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.-20+101C>G		intron_variant	Intron 1 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.505 AC: 71352 AN: 141246 Hom.: 20340 Cov.: 22

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.482

GnomAD2 exomes AF: 0.410 AC: 52592 AN: 128296 AF XY: 0.413

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.401 AC: 121234 AN: 302240 Hom.: 26073 Cov.: 0 AF XY: 0.410 AC XY: 70563 AN XY: 172198

African (AFR) AF: 0.820 AC: 7070 AN: 8624

American (AMR) AF: 0.363 AC: 9857 AN: 27152

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 4076 AN: 10750

East Asian (EAS) AF: 0.377 AC: 3439 AN: 9110

South Asian (SAS) AF: 0.528 AC: 31454 AN: 59606

European-Finnish (FIN) AF: 0.392 AC: 4826 AN: 12318

Middle Eastern (MID) AF: 0.427 AC: 1187 AN: 2778

European-Non Finnish (NFE) AF: 0.340 AC: 53713 AN: 157758

Other (OTH) AF: 0.397 AC: 5612 AN: 14144

GnomAD4 genome AF: 0.506 AC: 71461 AN: 141348 Hom.: 20395 Cov.: 22 AF XY: 0.509 AC XY: 34702 AN XY: 68192

African (AFR) AF: 0.818 AC: 32128 AN: 39264

American (AMR) AF: 0.428 AC: 5731 AN: 13396

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1252 AN: 3334

East Asian (EAS) AF: 0.387 AC: 1790 AN: 4624

South Asian (SAS) AF: 0.538 AC: 2377 AN: 4420

European-Finnish (FIN) AF: 0.440 AC: 3974 AN: 9026

Middle Eastern (MID) AF: 0.462 AC: 123 AN: 266

European-Non Finnish (NFE) AF: 0.356 AC: 22889 AN: 64234

Other (OTH) AF: 0.486 AC: 941 AN: 1938

Alfa AF: 0.298 Hom.: 1164

Bravo AF: 0.498

Asia WGS AF: 0.472 AC: 1642 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2

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 0.3304 (Asian), 0.1362 (African), 0.3694 (European), derived from 1000 genomes (2012-04-30). -

Jan 13, 2015

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.96
DANN	Benign	0.35
PhyloP100		-2.2
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs799905; hg19: chr17-41277187; COSMIC: COSV58786469; COSMIC: COSV58786469;