rs121964894

chr12-6036488-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 15P and 4B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong BS2

The NM_000552.5(VWF):c.2446C>T(p.Arg816Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R816Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 5.16

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain TIL 3 (size 51) in uniprot entity VWF_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000552.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6036487-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, VWF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 12-6036488-G-A is Pathogenic according to our data. Variant chr12-6036488-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6036488-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-6036488-G-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.2446C>T	p.Arg816Trp	missense_variant	19/52	ENST00000261405.10
VWF	XM_047429501.1	c.2446C>T	p.Arg816Trp	missense_variant	19/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.2446C>T	p.Arg816Trp	missense_variant	19/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-42554C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251368 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000850 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2023	Published functional studies demonstrate a damaging effect, including greatly decreased FVIIIB binding (van den Biggelaar et al., 2009; Qin et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also reported as R53W due to the use of alternative nomenclature; This variant is associated with the following publications: (PMID: 34708896, 26210168, 18728373, 1832934, 7847341, 28971901, 26988807, 21534937, 19088379, 31589614, 24351655) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2023	- -

Hereditary von Willebrand disease Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2019	The p.Arg816Trp variant in VWF has been reported in 6 homozygous, 4 compound heterozygous, and 2 heterozygous (only 1 allele identified) individuals with von Willebrand disease (VWD) and segregated with disease in at least 2 affected individuals from 1 family (Gaucher 1991, Johansson 2011, Qin 2014, Argyris 2016, Fidalgo 2016, Borras 2017). It has also been identified in 9/35418 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Qin 2004). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive VWD. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting. -

von Willebrand disease type 2N Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.59		Gain of catalytic residue at P811 (P = 0);
MVP		0.73
MPC		0.73
ClinPred		0.76	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.87

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: rs121964894; hg19: chr12-6145654;