rs764746353

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The ENST00000260947.9(BARD1):ā€‹c.325A>Gā€‹(p.Ser109Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S109R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

BARD1
ENST00000260947.9 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.68
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BS2
High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkuse as main transcriptc.325A>G p.Ser109Gly missense_variant 3/11 ENST00000260947.9 NP_000456.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.325A>G p.Ser109Gly missense_variant 3/111 NM_000465.4 ENSP00000260947 P2Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461378
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
726976
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 26, 2017In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BARD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 109 of the BARD1 protein (p.Ser109Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 02, 2024The c.325A>G variant (also known as p.S109G), located in coding exon 3 of the BARD1 gene, results from an A to G substitution at nucleotide position 325. The serine at codon 109 is replaced by glycine, an amino acid with similar properties. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame insertion of 1 amino acid and an in-frame deletion of 14 amino acid(s); however, the exact functional impact of the inserted and deleted amino acid(s) is unknown at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Benign
-0.34
CADD
Uncertain
25
DANN
Benign
0.93
DEOGEN2
Benign
0.12
T;.;.;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.79
T;T;T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.19
T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.8
M;.;.;M
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.6
N;.;.;.
REVEL
Benign
0.16
Sift
Benign
0.28
T;.;.;.
Sift4G
Benign
0.10
T;T;T;D
Polyphen
0.034
B;.;.;.
Vest4
0.41
MutPred
0.15
Loss of disorder (P = 0.086);Loss of disorder (P = 0.086);.;Loss of disorder (P = 0.086);
MVP
0.91
MPC
0.073
ClinPred
0.34
T
GERP RS
4.1
Varity_R
0.16
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.57
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.57
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764746353; hg19: chr2-215657060; API