10-114284921-C-T

Variant names:

• chr10-114284921-C-T
• rs140930475
• NM_001272046.2:c.948C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_001272046.2(VWA2):​c.948C>T​(p.Asp316Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,605,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: VWA2 NM_001272046.2 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.538

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]

AFAP1L2 (HGNC:25901): (actin filament associated protein 1 like 2) Enables SH2 domain binding activity; SH3 domain binding activity; and protein tyrosine kinase activator activity. Involved in several processes, including positive regulation of epidermal growth factor receptor signaling pathway; regulation of gene expression; and regulation of mitotic cell cycle. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01706487).
• BP6: Variant 10-114284921-C-T is Benign according to our data. Variant chr10-114284921-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3051730.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.538 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA2	NM_001272046.2	c.948C>T	p.Asp316Asp	synonymous_variant	Exon 10 of 14	ENST00000392982.8	NP_001258975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWA2	ENST00000392982.8	c.948C>T	p.Asp316Asp	synonymous_variant	Exon 10 of 14	1	NM_001272046.2	ENSP00000376708.3
VWA2	ENST00000603594.2	c.32C>T	p.Thr11Met	missense_variant	Exon 9 of 11	2		ENSP00000473752.2
VWA2	ENST00000298715.8	n.1198C>T		non_coding_transcript_exon_variant	Exon 10 of 12	2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000125 AC: 30 AN: 239534 Hom.: 0 AF XY: 0.000139 AC XY: 18 AN XY: 129828

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.000155

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000482

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 195 AN: 1453066 Hom.: 0 Cov.: 31 AF XY: 0.000126 AC XY: 91 AN XY: 722612

Gnomad4 AFR exome AF: 0.000638

Gnomad4 AMR exome AF: 0.000117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74494

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

VWA2-related disorder Benign:1

Feb 10, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.3
DANN	Benign	0.27
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.017	T
Polyphen		0.032	B
Vest4		0.10
MVP		0.23
GERP RS		-1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs140930475; hg19: chr10-116044680;