dbSNP rs1546585: BRCA1:c.-19-20494A>T (chr17-43144609-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000634433.2(BRCA1):c.-19-20494A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 166,114 control chromosomes in the GnomAD database, including 2,668 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 2661 hom., cov: 32)

Exomes 𝑓: 0.011 ( 7 hom. )

Consequence

BRCA1
ENST00000634433.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.385

Publications

4 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:

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]

NBR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
BRCA1	NM_001408458.1 link	c.-62+25517A>T	intron_variant	Intron 1 of 21	NP_001395387.1
NBR2	NR_003108.2 link	n.1012-119T>A	intron_variant	Intron 4 of 4
NBR2	NR_138145.1 link	n.1175+2033T>A	intron_variant	Intron 7 of 7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
BRCA1	ENST00000634433.2 link	c.-19-20494A>T	intron_variant	Intron 1 of 20	5	ENSP00000489431.2
NBR2	ENST00000460115.5 link	n.959-119T>A	intron_variant	Intron 4 of 4	2
NBR2	ENST00000467245.5 link	n.1088+2033T>A	intron_variant	Intron 7 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16107

AN:

152136

Hom.:

2641

Cov.:

show subpopulations

Gnomad AFR

AF:

0.352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0380

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.00885

Gnomad OTH

AF:

0.0750

GnomAD4 exome

AF:

0.0107

AC:

148

AN:

13860

Hom.:

AF XY:

0.0122

AC XY:

AN XY:

7458

show subpopulations

African (AFR)

AF:

0.304

AC:

AN:

American (AMR)

AF:

0.0204

AC:

AN:

1566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

102

East Asian (EAS)

AF:

0.00

AC:

AN:

316

South Asian (SAS)

AF:

0.0254

AC:

AN:

1692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2426

Middle Eastern (MID)

AF:

0.0500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00588

AC:

AN:

7138

Other (OTH)

AF:

0.0239

AC:

AN:

544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.106

AC:

16170

AN:

152254

Hom.:

2661

Cov.:

AF XY:

0.103

AC XY:

7656

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.353

AC:

14641

AN:

41486

American (AMR)

AF:

0.0378

AC:

579

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4830

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00885

AC:

602

AN:

68034

Other (OTH)

AF:

0.0742

AC:

157

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

573

1145

1718

2290

2863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0661

Hom.:

203

Bravo

AF:

0.120

Asia WGS

AF:

0.0410

AC:

143

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.8

(source)

DANN

Benign

0.78

PhyloP100

-0.39

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over