rs8176193

Variant names:

• chr17-43079499-C-T
• rs8176193
• NM_007294.4:c.4358-2885G>A

Variant summary

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

The NM_007294.4(BRCA1):​c.4358-2885G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,219,878 control chromosomes in the GnomAD database, including 76,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7934 hom., cov: 32)
  • Exomes 𝑓: 0.36 (68833 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.528
• Publications: 23 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]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 17-43079499-C-T is Benign according to our data. Variant chr17-43079499-C-T is described in ClinVar as Benign. ClinVar VariationId is 209399.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. 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_007294.4	MANE Select	c.4358-2885G>A		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.4358-100G>A		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.4358-100G>A		intron	N/A	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4358-2885G>A		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.4358-100G>A		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4358-2885G>A		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48067 AN: 151880 Hom.: 7928 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.356 AC: 380546 AN: 1067880 Hom.: 68833 Cov.: 16 AF XY: 0.361 AC XY: 198099 AN XY: 549010

African (AFR) AF: 0.241 AC: 6225 AN: 25846

American (AMR) AF: 0.320 AC: 14135 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 8853 AN: 23856

East Asian (EAS) AF: 0.355 AC: 13440 AN: 37908

South Asian (SAS) AF: 0.503 AC: 39680 AN: 78828

European-Finnish (FIN) AF: 0.392 AC: 15343 AN: 39152

Middle Eastern (MID) AF: 0.382 AC: 1891 AN: 4956

European-Non Finnish (NFE) AF: 0.345 AC: 264276 AN: 765660

Other (OTH) AF: 0.351 AC: 16703 AN: 47550

GnomAD4 genome AF: 0.316 AC: 48101 AN: 151998 Hom.: 7934 Cov.: 32 AF XY: 0.323 AC XY: 24016 AN XY: 74308

African (AFR) AF: 0.234 AC: 9708 AN: 41438

American (AMR) AF: 0.329 AC: 5027 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1245 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1910 AN: 5166

South Asian (SAS) AF: 0.493 AC: 2374 AN: 4820

European-Finnish (FIN) AF: 0.405 AC: 4274 AN: 10548

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22485 AN: 67976

Other (OTH) AF: 0.338 AC: 714 AN: 2110

Alfa AF: 0.312 Hom.: 977

Bravo AF: 0.302

Asia WGS AF: 0.418 AC: 1453 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
-	-	2	not provided (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.3
DANN	Benign	0.84
PhyloP100		0.53
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: rs8176193; hg19: chr17-41231516; COSMIC: COSV58789905;