rs143914387

Variant names:

• chr2-214809537-C-A
• rs143914387
• NM_000465.4:c.33G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-214809537-C-A
• chr2-214809537-C-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000465.4(BARD1):​c.33G>T​(p.Gln11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,577,884 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:23
• Conservation: PhyloP100: 0.100
• Publications: 11 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]

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 54 uncertain in NM_000465.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070047975).
• BP6: Variant 2-214809537-C-A is Benign according to our data. Variant chr2-214809537-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127737.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00165 (252/152328) while in subpopulation AMR AF = 0.00255 (39/15310). AF 95% confidence interval is 0.00192. There are 0 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 252 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.33G>T	p.Gln11His	missense	Exon 1 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.33G>T	p.Gln11His	missense	Exon 1 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.33G>T	p.Gln11His	missense	Exon 1 of 7	NP_001269474.1	C9IYG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.33G>T	p.Gln11His	missense	Exon 1 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.33G>T	p.Gln11His	missense	Exon 1 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.33G>T	p.Gln11His	missense	Exon 1 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00161 AC: 304 AN: 188348 AF XY: 0.00161

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.000671

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00284

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00156 AC: 2229 AN: 1425556 Hom.: 5 Cov.: 74 AF XY: 0.00152 AC XY: 1074 AN XY: 706906

African (AFR) AF: 0.000245 AC: 8 AN: 32622

American (AMR) AF: 0.00257 AC: 107 AN: 41698

Ashkenazi Jewish (ASJ) AF: 0.000743 AC: 19 AN: 25562

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37866

South Asian (SAS) AF: 0.000420 AC: 35 AN: 83408

European-Finnish (FIN) AF: 0.00315 AC: 138 AN: 43874

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5682

European-Non Finnish (NFE) AF: 0.00166 AC: 1821 AN: 1095852

Other (OTH) AF: 0.00156 AC: 92 AN: 58992

GnomAD4 genome AF: 0.00165 AC: 252 AN: 152328 Hom.: 0 Cov.: 34 AF XY: 0.00200 AC XY: 149 AN XY: 74488

African (AFR) AF: 0.000192 AC: 8 AN: 41592

American (AMR) AF: 0.00255 AC: 39 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.219 Hom.: 6855

Bravo AF: 0.00150

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00241 AC: 19

ExAC AF: 0.00162 AC: 189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not provided (10)
-	-	7	Familial cancer of breast (7)
-	1	3	Hereditary cancer-predisposing syndrome (4)
-	1	1	not specified (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.10
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.16
Sift	Benign	0.17	T
Sift4G	Benign	0.082	T
Polyphen		0.41	B
Vest4		0.24
MutPred		0.073		Loss of stability (P = 0.1698)
MVP		0.93
MPC		0.12
ClinPred		0.013	T
GERP RS		-0.27
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.13
gMVP		0.49
Mutation Taster		=99/1	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: rs143914387; hg19: chr2-215674261;