rs748828467

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_000465.4(BARD1):c.188T>C(p.Leu63Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,612,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L63V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.72

Publications

6 publications found

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]

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

BARD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 38 uncertain in NM_000465.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

BS2

High AC in GnomAdExome4 at 14 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BARD1	NM_000465.4	MANE Select	c.188T>C	p.Leu63Ser	missense	Exon 2 of 11	NP_000456.2	Q99728-1
BARD1	NM_001282545.2		c.188T>C	p.Leu63Ser	missense	Exon 2 of 7	NP_001269474.1	C9IYG1
BARD1	NM_001282549.2		c.188T>C	p.Leu63Ser	missense	Exon 2 of 5	NP_001269478.1	A0A087WZ19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BARD1	ENST00000260947.9	TSL:1 MANE Select	c.188T>C	p.Leu63Ser	missense	Exon 2 of 11	ENSP00000260947.4	Q99728-1
BARD1	ENST00000613706.5	TSL:1	c.188T>C	p.Leu63Ser	missense	Exon 2 of 11	ENSP00000484976.2	A0A087X2H0
BARD1	ENST00000619009.5	TSL:1	c.188T>C	p.Leu63Ser	missense	Exon 2 of 5	ENSP00000482293.1	A0A087WZ19

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251160

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460766

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111160

Other (OTH)

AF:

0.0000166

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

BARD1-related cancer predisposition (1)

Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.4

PhyloP100

5.7

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.97

Vest4

0.60

MutPred

0.63

Gain of glycosylation at L63 (P = 0.0242)

MVP

0.98

MPC

0.47

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.86

gMVP

0.85

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over