rs1800377

chr12-6064267-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):c.1411G>A(p.Val471Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,614,044 control chromosomes in the GnomAD database, including 11,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1091 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10753 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00400

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015455186).
• BP6: Variant 12-6064267-C-T is Benign according to our data. Variant chr12-6064267-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.1411G>A	p.Val471Ile	missense_variant	12/52	ENST00000261405.10
VWF	XM_047429501.1	c.1411G>A	p.Val471Ile	missense_variant	12/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.1411G>A	p.Val471Ile	missense_variant	12/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.420+46248G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17587 AN: 152142 Hom.: 1092 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.0930

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0918

GnomAD3 exomes AF: 0.114 AC: 28579 AN: 250654 Hom.: 1926 AF XY: 0.118 AC XY: 16043 AN XY: 135598

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0483

Gnomad ASJ exome AF: 0.0507

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.0983

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.117 AC: 171222 AN: 1461782 Hom.: 10753 Cov.: 33 AF XY: 0.119 AC XY: 86576 AN XY: 727192

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0501

Gnomad4 ASJ exome AF: 0.0490

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.0995

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.116 AC: 17590 AN: 152262 Hom.: 1091 Cov.: 33 AF XY: 0.114 AC XY: 8474 AN XY: 74460

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.0623

Gnomad4 ASJ AF: 0.0424

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.0930

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.0908

Alfa AF: 0.111 Hom.: 1572

Bravo AF: 0.112

TwinsUK AF: 0.115 AC: 427

ALSPAC AF: 0.111 AC: 428

ESP6500AA AF: 0.139 AC: 611

ESP6500EA AF: 0.110 AC: 948

ExAC AF: 0.118 AC: 14348

Asia WGS AF: 0.166 AC: 576 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 11, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

von Willebrand disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	4.2
Dann	Benign	0.40
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.055	N
MutationTaster	Benign	0.92	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.13
Sift	Benign	0.96	T
Sift4G	Benign	1.0	T
Polyphen		0.019	B
Vest4		0.038
MPC		0.21
ClinPred		0.0031	T
GERP RS		-2.9
Varity_R		0.032
gMVP		0.12

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: rs1800377; hg19: chr12-6173433;