chr2-214728557-C-T

Variant names:

• chr2-214728557-C-T
• rs1378645134
• ENST00000471590.5:n.788G>A

Variant summary

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

The ENST00000471590.5(BARD1):​n.788G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.00025 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 ENST00000471590.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.866
• Publications: 0 publications found

Genes affected

BARD1 (HGNC:952): (BRCA1 associated RING domain 1) This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

BARD1 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.*119G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.*119G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.000248 AC: 30 AN: 120766 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000927

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00298

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000174

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000452 AC: 235 AN: 520124 Hom.: 0 Cov.: 10 AF XY: 0.000482 AC XY: 127 AN XY: 263462

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

African (AFR) AF: 0.000480 AC: 6 AN: 12492

American (AMR) AF: 0.000559 AC: 7 AN: 12518

Ashkenazi Jewish (ASJ) AF: 0.000233 AC: 3 AN: 12898

East Asian (EAS) AF: 0.000369 AC: 9 AN: 24392

South Asian (SAS) AF: 0.00143 AC: 40 AN: 27926

European-Finnish (FIN) AF: 0.000482 AC: 11 AN: 22826

Middle Eastern (MID) AF: 0.00111 AC: 3 AN: 2692

European-Non Finnish (NFE) AF: 0.000367 AC: 139 AN: 378506

Other (OTH) AF: 0.000657 AC: 17 AN: 25874

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000248 AC: 30 AN: 120806 Hom.: 0 Cov.: 30 AF XY: 0.000209 AC XY: 12 AN XY: 57358

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

African (AFR) AF: 0.0000925 AC: 3 AN: 32442

American (AMR) AF: 0.0000852 AC: 1 AN: 11734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3078

East Asian (EAS) AF: 0.00 AC: 0 AN: 4180

South Asian (SAS) AF: 0.00 AC: 0 AN: 3818

European-Finnish (FIN) AF: 0.00298 AC: 16 AN: 5378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.000174 AC: 10 AN: 57512

Other (OTH) AF: 0.00 AC: 0 AN: 1672

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Benign:1

May 28, 2019

Mendelics

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	-0.82
CADD	Benign	1.4
DANN	Benign	0.40
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism

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: rs1378645134; hg19: chr2-215593281;