chr2-214754055-A-G

Variant names:

• chr2-214754055-A-G
• rs1374230
• NM_000465.4:c.1569-1500T>C

Variant summary

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

The NM_000465.4(BARD1):​c.1569-1500T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,032 control chromosomes in the GnomAD database, including 7,678 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 0.31 (7678 hom., cov: 32)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.120
• Publications: 9 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1569-1500T>C		intron_variant	Intron 6 of 10	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1569-1500T>C		intron_variant	Intron 6 of 10	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47661 AN: 151914 Hom.: 7664 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.306

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

GnomAD4 genome AF: 0.314 AC: 47700 AN: 152032 Hom.: 7678 Cov.: 32 AF XY: 0.320 AC XY: 23787 AN XY: 74308

African (AFR) AF: 0.311 AC: 12912 AN: 41476

American (AMR) AF: 0.283 AC: 4310 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1063 AN: 3470

East Asian (EAS) AF: 0.349 AC: 1803 AN: 5168

South Asian (SAS) AF: 0.399 AC: 1922 AN: 4820

European-Finnish (FIN) AF: 0.406 AC: 4297 AN: 10584

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20440 AN: 67960

Other (OTH) AF: 0.308 AC: 648 AN: 2104

Alfa AF: 0.274 Hom.: 2055

Bravo AF: 0.298

Asia WGS AF: 0.357 AC: 1241 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.55
PhyloP100		-0.12
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: rs1374230; hg19: chr2-215618779;