rs76824305

Variant names:

• chr2-214780609-A-C
• rs76824305
• NM_000465.4:c.1265T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-214780609-A-C
• chr2-214780609-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000465.4(BARD1):​c.1265T>G​(p.Val422Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V422M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.558
• Publications: 4 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):

• BARD1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast cancer

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060567647).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.1265T>G	p.Val422Gly	missense	Exon 4 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.1208T>G	p.Val403Gly	missense	Exon 3 of 10	NP_001269472.1
	BARD1	NM_001282545.2		c.215+16452T>G		intron	N/A	NP_001269474.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.1265T>G	p.Val422Gly	missense	Exon 4 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.1208T>G	p.Val403Gly	missense	Exon 3 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.906+359T>G		intron	N/A	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250634 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1461598 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727084

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000313 AC: 38

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.2
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.56
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.051
Sift	Uncertain	0.011	D
Sift4G	Benign	0.30	T
Polyphen		0.0020	B
Vest4		0.072
MutPred		0.49		Loss of stability (P = 0.0047)
MVP		0.59
MPC		0.098
ClinPred		0.031	T
GERP RS		0.40
Varity_R		0.13
gMVP		0.35
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76824305; hg19: chr2-215645333; COSMIC: COSV53613184; COSMIC: COSV53613184;