2-214728537-CTTTTTT-CTTTT

Variant names:

• chr2-214728537-CTT-C
• rs113789798
• ENST00000471590.5:n.806_807delAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000471590.5(BARD1):​n.806_807delAA variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 582,996 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0090 (0 hom.)
• Consequence: BARD1 ENST00000471590.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 1 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00025 (36/143986) while in subpopulation AFR AF = 0.000659 (26/39446). AF 95% confidence interval is 0.000461. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.*137_*138delAA		3_prime_UTR_variant	Exon 11 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.*137_*138delAA		3_prime_UTR_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 36 AN: 143960 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000660

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000687

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000907

Gnomad OTH AF: 0.000508

GnomAD4 exome AF: 0.00898 AC: 3944 AN: 439010 Hom.: 0 AF XY: 0.00886 AC XY: 2015 AN XY: 227520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0180 AC: 212 AN: 11802

American (AMR) AF: 0.0119 AC: 175 AN: 14718

Ashkenazi Jewish (ASJ) AF: 0.00630 AC: 77 AN: 12218

East Asian (EAS) AF: 0.00434 AC: 116 AN: 26746

South Asian (SAS) AF: 0.00848 AC: 282 AN: 33272

European-Finnish (FIN) AF: 0.00592 AC: 143 AN: 24174

Middle Eastern (MID) AF: 0.0131 AC: 30 AN: 2290

European-Non Finnish (NFE) AF: 0.00930 AC: 2695 AN: 289812

Other (OTH) AF: 0.00892 AC: 214 AN: 23978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000250 AC: 36 AN: 143986 Hom.: 0 Cov.: 0 AF XY: 0.000215 AC XY: 15 AN XY: 69636

African (AFR) AF: 0.000659 AC: 26 AN: 39446

American (AMR) AF: 0.0000687 AC: 1 AN: 14562

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4986

South Asian (SAS) AF: 0.00 AC: 0 AN: 4570

European-Finnish (FIN) AF: 0.000130 AC: 1 AN: 7676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000907 AC: 6 AN: 66158

Other (OTH) AF: 0.000505 AC: 1 AN: 1980

Alfa AF: 0.00 Hom.: 739

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism

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: rs113789798; hg19: chr2-215593261;