NM_000465.4:c.159-5063A>G

Variant names:

• chr2-214802180-T-C
• rs6712055
• NM_000465.4:c.159-5063A>G

Variant summary

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

The NM_000465.4(BARD1):​c.159-5063A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 152,154 control chromosomes in the GnomAD database, including 6,392 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 0.28 (6392 hom., cov: 32)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.465
• Publications: 12 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.159-5063A>G		intron_variant	Intron 1 of 10	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.159-5063A>G		intron_variant	Intron 1 of 10	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41942 AN: 152036 Hom.: 6392 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.279

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

GnomAD4 genome AF: 0.276 AC: 41945 AN: 152154 Hom.: 6392 Cov.: 32 AF XY: 0.281 AC XY: 20937 AN XY: 74390

African (AFR) AF: 0.173 AC: 7165 AN: 41520

American (AMR) AF: 0.274 AC: 4187 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1147 AN: 3468

East Asian (EAS) AF: 0.579 AC: 2996 AN: 5176

South Asian (SAS) AF: 0.377 AC: 1818 AN: 4818

European-Finnish (FIN) AF: 0.356 AC: 3761 AN: 10572

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.293 AC: 19942 AN: 67988

Other (OTH) AF: 0.284 AC: 599 AN: 2112

Alfa AF: 0.295 Hom.: 9661

Bravo AF: 0.270

Asia WGS AF: 0.452 AC: 1575 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.0
DANN	Benign	0.69
PhyloP100		-0.47
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: rs6712055; hg19: chr2-215666904;