rs8176193

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: 0.528

Publications

23 publications found

Variant links:

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]

BRCA1 links:

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

RPL21P4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.4358-2885G>A		intron_variant	Intron 12 of 22	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.4358-2885G>A		intron_variant	Intron 12 of 22	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.316

AC:

48067

AN:

151880

Hom.:

7928

Cov.:

show subpopulations

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.:

AF XY:

0.361

AC XY:

198099

AN XY:

549010

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

13842

27684

41525

55367

69209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7358

14716

22074

29432

36790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.316

AC:

48101

AN:

151998

Hom.:

7934

Cov.:

AF XY:

0.323

AC XY:

24016

AN XY:

74308

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1692

3384

5075

6767

8459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

498

996

1494

1992

2490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.312

Hom.:

977

Bravo

AF:

0.302

Asia WGS

AF:

0.418

AC:

1453

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

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), 0.2154 (African), 0.3588 (European), derived from 1000 genomes (2012-04-30). -

GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

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

-0.66

CADD

Benign

6.3

(source)

DANN

Benign

0.84

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over