chr17-43044804-CT-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_007294.4(BRCA1):c.*873delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.19 ( 1131 hom., cov: 0)

Exomes 𝑓: 0.18 ( 21 hom. )

Failed GnomAD Quality Control

Consequence

BRCA1
NM_007294.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 0.446

Publications

3 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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 17-43044804-CT-C is Benign according to our data. Variant chr17-43044804-CT-C is described in ClinVar as [Benign]. Clinvar id is 264856.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High Homozygotes in GnomAdExome4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.*873delA		3_prime_UTR_variant	Exon 23 of 23	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.*873delA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

23344

AN:

121312

Hom.:

1131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.0633

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.154

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.187

AC:

9224

AN:

49390

AF XY:

0.184

show subpopulations

Gnomad AFR exome

AF:

0.234

Gnomad AMR exome

AF:

0.201

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.202

GnomAD4 exome

AF:

0.178

AC:

44598

AN:

250200

Hom.:

Cov.:

AF XY:

0.177

AC XY:

25187

AN XY:

142054

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.197

AC:

1127

AN:

5718

American (AMR)

AF:

0.167

AC:

2554

AN:

15332

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

1562

AN:

8932

East Asian (EAS)

AF:

0.129

AC:

1552

AN:

12000

South Asian (SAS)

AF:

0.156

AC:

7197

AN:

46142

European-Finnish (FIN)

AF:

0.155

AC:

1470

AN:

9490

Middle Eastern (MID)

AF:

0.195

AC:

177

AN:

906

European-Non Finnish (NFE)

AF:

0.192

AC:

26794

AN:

139598

Other (OTH)

AF:

0.179

AC:

2165

AN:

12082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.313

Heterozygous variant carriers

3046

6092

9139

12185

15231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.192

AC:

23340

AN:

121322

Hom.:

1131

Cov.:

AF XY:

0.188

AC XY:

10802

AN XY:

57358

show subpopulations

African (AFR)

AF:

0.207

AC:

6554

AN:

31626

American (AMR)

AF:

0.163

AC:

1903

AN:

11652

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

680

AN:

3062

East Asian (EAS)

AF:

0.0630

AC:

278

AN:

4414

South Asian (SAS)

AF:

0.167

AC:

600

AN:

3588

European-Finnish (FIN)

AF:

0.154

AC:

799

AN:

5194

Middle Eastern (MID)

AF:

0.241

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.203

AC:

12005

AN:

59084

Other (OTH)

AF:

0.196

AC:

323

AN:

1644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

767

1535

2302

3070

3837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0514

Hom.:

100

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:1

Sep 28, 2016

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 0.5358 (European), 0.4924 (African), 0.464 (Admixed American/Latino), 0.4583 (East Asian), 0.5521 (South Asian), derived from 1000 genomes (2013-05-02). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.45

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

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

Publications

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chr17-43044804-CT-C

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