rs17165936

chr7-12375099-G-Achr7-12375099-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BA1

The NM_001135924.3(VWDE):c.1153C>T(p.Arg385Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,550,886 control chromosomes in the GnomAD database, including 13,149 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.14 (1619 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11530 hom.)
• Consequence: VWDE NM_001135924.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

Genes affected

VWDE (HGNC:21897): (von Willebrand factor D and EGF domains) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM4: Stoplost variant in NM_001135924.3 Downstream stopcodon found after 4 codons.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.1153C>T	p.Arg385Ter	stop_gained	8/29	ENST00000275358.8
VWDE	NM_001346972.2	c.1153C>T	p.Arg385Ter	stop_gained	8/27
VWDE	NM_001346973.2	c.688C>T	p.Arg230Ter	stop_gained	8/27
VWDE	NR_144534.2	n.1302C>T		non_coding_transcript_exon_variant	8/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.1153C>T	p.Arg385Ter	stop_gained	8/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.1153C>T	p.Arg385Ter	stop_gained, NMD_transcript_variant	8/30	1
VWDE	ENST00000521169.5	c.1024+2677C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20675 AN: 151890 Hom.: 1618 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0787

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.124 AC: 19531 AN: 156890 Hom.: 1441 AF XY: 0.130 AC XY: 10823 AN XY: 83028

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0947

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.0979

GnomAD4 exome AF: 0.124 AC: 172887 AN: 1398878 Hom.: 11530 Cov.: 32 AF XY: 0.125 AC XY: 86490 AN XY: 689944

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.0620

Gnomad4 ASJ exome AF: 0.0902

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.136 AC: 20693 AN: 152008 Hom.: 1619 Cov.: 32 AF XY: 0.137 AC XY: 10181 AN XY: 74308

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.0787

Gnomad4 ASJ AF: 0.0866

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.108

Alfa AF: 0.117 Hom.: 2145

Bravo AF: 0.135

TwinsUK AF: 0.112 AC: 416

ALSPAC AF: 0.122 AC: 471

ESP6500AA AF: 0.209 AC: 289

ESP6500EA AF: 0.114 AC: 362

ExAC AF: 0.141 AC: 3476

Asia WGS AF: 0.178 AC: 617 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	2.7e-24	P
Vest4		0.070
GERP RS		3.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs17165936; hg19: chr7-12414725; COSMIC: COSV51725678; COSMIC: COSV51725678;