10-114255010-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001272046.2(VWA2):c.223A>T(p.Ile75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,613,002 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (15 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (82 hom.)
• Consequence: VWA2 NM_001272046.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.504

Genes affected

VWA2 (HGNC:24709): (von Willebrand factor A domain containing 2) This gene encodes a member of the von Willebrand factor A-like domain protein superfamily. The encoded protein is localized to the extracellular matrix and may serve as a structural component in basement membranes or in anchoring structures on scaffolds of collagen VII or fibrillin. This gene has been linked to type 1A diabetes and is a candidate serological marker for colon cancer. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033477843).
• BP6: Variant 10-114255010-A-T is Benign according to our data. Variant chr10-114255010-A-T is described in ClinVar as [Benign]. Clinvar id is 708371.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00537 (818/152270) while in subpopulation EAS AF= 0.054 (279/5168). AF 95% confidence interval is 0.0488. There are 15 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA2	NM_001272046.2	c.223A>T	p.Ile75Phe	missense_variant	4/14	ENST00000392982.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA2	ENST00000392982.8	c.223A>T	p.Ile75Phe	missense_variant	4/14	1	NM_001272046.2	P1
VWA2	ENST00000603594.2	c.-656+1285A>T		intron_variant		2
VWA2	ENST00000298715.8	n.473A>T		non_coding_transcript_exon_variant	4/12	2

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152152 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0542

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.0112 AC: 2798 AN: 250608 Hom.: 53 AF XY: 0.00948 AC XY: 1288 AN XY: 135810

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.0620

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00883

GnomAD4 exome AF: 0.00329 AC: 4800 AN: 1460732 Hom.: 82 Cov.: 30 AF XY: 0.00305 AC XY: 2214 AN XY: 726638

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.0295

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0483

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.00537 AC: 818 AN: 152270 Hom.: 15 Cov.: 31 AF XY: 0.00622 AC XY: 463 AN XY: 74464

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0540

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0157

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.000974 Hom.: 0

Bravo AF: 0.00620

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00957 AC: 1161

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.74	D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.45
Sift	Benign	0.22	T
Sift4G	Benign	0.080	T
Polyphen		0.95	P
Vest4		0.41
ClinPred		0.037	T
GERP RS		-0.39
Varity_R		0.21
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs75028145; hg19: chr10-116014769; COSMIC: COSV53905590;