NM_000465.4:c.364+3134A>G

Variant names:

• chr2-214789163-T-C
• rs7587476
• NM_000465.4:c.364+3134A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000465.4(BARD1):​c.364+3134A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 152,032 control chromosomes in the GnomAD database, including 41,153 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (41153 hom., cov: 31)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 30 publications found

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):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.364+3134A>G		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.307+3134A>G		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.215+7898A>G		intron	N/A	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.364+3134A>G		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.307+3134A>G		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.364+3134A>G		intron	N/A	ENSP00000484976.2

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111343 AN: 151914 Hom.: 41118 Cov.: 31

Gnomad AFR AF: 0.653

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.688

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.728

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.733 AC: 111432 AN: 152032 Hom.: 41153 Cov.: 31 AF XY: 0.738 AC XY: 54876 AN XY: 74340

African (AFR) AF: 0.653 AC: 27037 AN: 41430

American (AMR) AF: 0.725 AC: 11063 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 2616 AN: 3472

East Asian (EAS) AF: 0.792 AC: 4100 AN: 5178

South Asian (SAS) AF: 0.689 AC: 3324 AN: 4824

European-Finnish (FIN) AF: 0.858 AC: 9085 AN: 10586

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51744 AN: 67964

Other (OTH) AF: 0.731 AC: 1544 AN: 2112

Alfa AF: 0.748 Hom.: 90778

Bravo AF: 0.718

Asia WGS AF: 0.737 AC: 2562 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.95
DANN	Benign	0.80
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7587476; hg19: chr2-215653887;