17-43125313-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000354071.8(BRCA1):n.3G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 455,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

BRCA1
ENST00000354071.8 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.139

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000354071.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BRCA1	NM_007294.4	MANE Select	c.-62G>A	5_prime_UTR	Exon 1 of 23	NP_009225.1
BRCA1	NM_001407581.1		c.-62G>A	5_prime_UTR	Exon 1 of 24	NP_001394510.1
BRCA1	NM_001407582.1		c.-151G>A	5_prime_UTR	Exon 1 of 24	NP_001394511.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BRCA1	ENST00000354071.8	TSL:1	n.3G>A	non_coding_transcript_exon	Exon 1 of 10
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.-62G>A	5_prime_UTR	Exon 1 of 23	ENSP00000350283.3
BRCA1	ENST00000471181.7	TSL:1	c.-62G>A	5_prime_UTR	Exon 1 of 24	ENSP00000418960.2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000230

AC:

AN:

130572

AF XY:

0.0000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000601

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

303734

Hom.:

Cov.:

AF XY:

0.0000347

AC XY:

AN XY:

172932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8626

American (AMR)

AF:

0.00

AC:

AN:

27262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10784

East Asian (EAS)

AF:

0.00

AC:

AN:

9200

South Asian (SAS)

AF:

0.00

AC:

AN:

59730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2776

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

158768

Other (OTH)

AF:

0.0000703

AC:

AN:

14220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000642

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

-0.14

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over