2-214728509-T-C

Position:

• chr2-214728509-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000465.4(BARD1):​c.*167A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 674,652 control chromosomes in the GnomAD database, including 127,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (31816 hom., cov: 28)
  • Exomes 𝑓: 0.60 (95513 hom.)
• Consequence: BARD1 NM_000465.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.48

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-214728509-T-C is Benign according to our data. Variant chr2-214728509-T-C is described in ClinVar as [Benign]. Clinvar id is 1222105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.*167A>G		3_prime_UTR_variant	11/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.*167A>G		3_prime_UTR_variant	11/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.645 AC: 96663 AN: 149756 Hom.: 31782 Cov.: 28

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.605

GnomAD4 exome AF: 0.598 AC: 313693 AN: 524820 Hom.: 95513 Cov.: 7 AF XY: 0.596 AC XY: 163425 AN XY: 274258

Gnomad4 AFR exome AF: 0.767

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.565

Gnomad4 FIN exome AF: 0.674

Gnomad4 NFE exome AF: 0.611

Gnomad4 OTH exome AF: 0.598

GnomAD4 genome AF: 0.646 AC: 96738 AN: 149832 Hom.: 31816 Cov.: 28 AF XY: 0.644 AC XY: 47035 AN XY: 72990

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.560

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.583

Gnomad4 FIN AF: 0.688

Gnomad4 NFE AF: 0.612

Gnomad4 OTH AF: 0.607

Alfa AF: 0.631 Hom.: 6641

Bravo AF: 0.633

Asia WGS AF: 0.525 AC: 1824 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.8
DANN	Benign	0.85

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

LitVar

Other links and lift over

dbSNP: rs5020511; hg19: chr2-215593233;