rs863224674

chr2-214809499-G-Achr2-214809499-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000465.4(BARD1):c.71C>T(p.Pro24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. P24A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.71C>T	p.Pro24Leu	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.71C>T	p.Pro24Leu	missense_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 77

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.081	T;.;.;.;T;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;.
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.5	L;.;L;.;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N;.;.;.;.;.;N
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;.;.;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		0.15	B;.;.;.;.;.;.
Vest4		0.17
MutPred		0.14		Loss of glycosylation at P24 (P = 0.0565);Loss of glycosylation at P24 (P = 0.0565);Loss of glycosylation at P24 (P = 0.0565);Loss of glycosylation at P24 (P = 0.0565);Loss of glycosylation at P24 (P = 0.0565);Loss of glycosylation at P24 (P = 0.0565);Loss of glycosylation at P24 (P = 0.0565);
MVP		0.88
MPC		0.077
ClinPred		0.65	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs863224674; hg19: chr2-215674223;