chr17-43079681-G-C

Position:

• chr17-43079681-G-C

Variant summary

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

The NM_007294.4(BRCA1):​c.4357+2723C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,039,556 control chromosomes in the GnomAD database, including 7,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.13 (4368 hom., cov: 31)
  • Exomes 𝑓: 0.024 (2717 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 1.23

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]

RPL21P4 (HGNC:17959): (ribosomal protein L21 pseudogene 4)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-43079681-G-C is Benign according to our data. Variant chr17-43079681-G-C is described in ClinVar as [Benign]. Clinvar id is 209400.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43079681-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4357+2723C>G		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4357+2723C>G		intron_variant		1	NM_007294.4	ENSP00000350283	P4
RPL21P4	ENST00000497954.1	n.380G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20389 AN: 151710 Hom.: 4346 Cov.: 31

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0469

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00926

Gnomad OTH AF: 0.0920

GnomAD4 exome AF: 0.0239 AC: 21174 AN: 887728 Hom.: 2717 Cov.: 13 AF XY: 0.0219 AC XY: 10205 AN XY: 465478

Gnomad4 AFR exome AF: 0.459

Gnomad4 AMR exome AF: 0.0278

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.0284

Gnomad4 FIN exome AF: 0.00132

Gnomad4 NFE exome AF: 0.00892

Gnomad4 OTH exome AF: 0.0426

GnomAD4 genome AF: 0.135 AC: 20459 AN: 151828 Hom.: 4368 Cov.: 31 AF XY: 0.130 AC XY: 9672 AN XY: 74234

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.0467

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.00152

Gnomad4 NFE AF: 0.00927

Gnomad4 OTH AF: 0.0911

Alfa AF: 0.0835 Hom.: 325

Bravo AF: 0.152

Asia WGS AF: 0.0480 AC: 168 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 0.5 (African), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.91
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs8176192; hg19: chr17-41231698;