2-214728537-C-CTTT

Position:

• chr2-214728537-C-CTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000465.4(BARD1):​c.*138_*139insAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (39 hom., cov: 0)
  • Exomes 𝑓: 0.023 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 NM_000465.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.392

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-214728537-C-CTTT is Benign according to our data. Variant chr2-214728537-C-CTTT is described in ClinVar as [Likely_benign]. Clinvar id is 801874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0228 (10091/441932) while in subpopulation NFE AF= 0.0245 (7146/291462). AF 95% confidence interval is 0.024. There are 7 homozygotes in gnomad4_exome. There are 5176 alleles in male gnomad4_exome subpopulation. Median coverage is 6. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 10091 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.*138_*139insAAA		3_prime_UTR_variant	11/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.*138_*139insAAA		3_prime_UTR_variant	11/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2620 AN: 143954 Hom.: 39 Cov.: 0

Gnomad AFR AF: 0.00564

Gnomad AMI AF: 0.0487

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0371

Gnomad EAS AF: 0.00160

Gnomad SAS AF: 0.0146

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0227

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0218

GnomAD4 exome AF: 0.0228 AC: 10091 AN: 441932 Hom.: 7 Cov.: 6 AF XY: 0.0226 AC XY: 5176 AN XY: 229074

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.00573

Gnomad4 SAS exome AF: 0.0244

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0221

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0182 AC: 2618 AN: 143982 Hom.: 39 Cov.: 0 AF XY: 0.0168 AC XY: 1169 AN XY: 69640

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0371

Gnomad4 EAS AF: 0.00160

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0267

Gnomad4 OTH AF: 0.0217

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2019

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113789798; hg19: chr2-215593261;