rs786201482

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000465.4(BARD1):c.-4G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000512 in 1,544,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

BARD1
NM_000465.4 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 1.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-214809573-C-T is Benign according to our data. Variant chr2-214809573-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184470.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=1}.

BS2

High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.-4G>A		5_prime_UTR_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.-4G>A		5_prime_UTR_variant	1/11	1	NM_000465.4	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

149958

Hom.:

AF XY:

0.0000365

AC XY:

AN XY:

82200

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000988

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000517

AC:

AN:

1391892

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

687232

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:

0.0000648

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000904

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 10, 2023	The variant has not been reported in individuals with BARD1-related conditions in the published literature. The frequency of this variant in the general population, 0.000092 (7/76156 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2017	Variant summary: The BARD1 c.-4G>A variant involves the alteration of a non-conserved nucleotide in the 5UTR region. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 18828 control chromosomes. In addition, another clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2022	The c.-4G>A variant is located in the 5' untranslated region (5’ UTR) of the BARD1 gene. This variant results from a G to A substitution 4 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BARD1 c.-4G>A variant was not identified in the literature nor was it identified in the COSMIC, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs761863671) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, and in the ClinVar and Clinvitae databases (1x classified as uncertain significance by Ambry Genetics). The variant was identified in control databases in 7 of 176022 chromosomes (no homozygotes) at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 7 of 73398 chromosomes (freq: 0.000095), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The c.-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

BARD1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

Cadd

Benign

Dann

Benign

0.94

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over