rs16852689

Variant names:

• chr2-214770549-C-T
• rs16852689
• NM_000465.4:c.1315-1237G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000465.4(BARD1):​c.1315-1237G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,256 control chromosomes in the GnomAD database, including 1,429 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 0.13 (1429 hom., cov: 33)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1315-1237G>A		intron_variant	Intron 4 of 10	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1315-1237G>A		intron_variant	Intron 4 of 10	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20132 AN: 152138 Hom.: 1422 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.148

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.132 AC: 20163 AN: 152256 Hom.: 1429 Cov.: 33 AF XY: 0.131 AC XY: 9716 AN XY: 74450

African (AFR) AF: 0.163 AC: 6783 AN: 41540

American (AMR) AF: 0.153 AC: 2334 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3470

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5186

South Asian (SAS) AF: 0.0710 AC: 343 AN: 4828

European-Finnish (FIN) AF: 0.0821 AC: 870 AN: 10598

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8972 AN: 68028

Other (OTH) AF: 0.147 AC: 310 AN: 2108

Alfa AF: 0.130 Hom.: 4254

Bravo AF: 0.137

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.80
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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: rs16852689; hg19: chr2-215635273;