chr2-214809568-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000465.4(BARD1):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Consequence

BARD1
NM_000465.4 start_lost

Scores

6
2
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.27
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000465.4 (BARD1) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkc.2T>A p.Met1? start_lost 1/11 ENST00000260947.9 NP_000456.2 Q99728-1A0AVN2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkc.2T>A p.Met1? start_lost 1/111 NM_000465.4 ENSP00000260947.4 Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
73
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.058
T;.;.;.;T;.;.
Eigen
Benign
0.15
Eigen_PC
Benign
0.14
FATHMM_MKL
Benign
0.56
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;.
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Benign
-0.30
T
PROVEAN
Benign
-0.39
N;.;.;.;.;.;N
REVEL
Uncertain
0.49
Sift
Pathogenic
0.0
D;.;.;.;.;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Polyphen
0.90
P;.;.;.;.;.;.
Vest4
0.80
MutPred
0.98
Loss of stability (P = 0.0343);Loss of stability (P = 0.0343);Loss of stability (P = 0.0343);Loss of stability (P = 0.0343);Loss of stability (P = 0.0343);Loss of stability (P = 0.0343);Loss of stability (P = 0.0343);
MVP
0.91
ClinPred
0.99
D
GERP RS
4.0
Varity_R
0.97
gMVP
0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-215674292; API