NM_000552.5:c.2771G>A

Variant names:

• chr12-6031493-C-T
• rs33978901
• NM_000552.5:c.2771G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000552.5(VWF):​c.2771G>A​(p.Arg924Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,614,096 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R924W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 31)
  • Exomes 𝑓: 0.018 (284 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9 O:1
• Conservation: PhyloP100: 0.511
• Publications: 31 publications found

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]

VWF Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease 1, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease type 2M, von Willebrand disease 3, von Willebrand disease type 2N.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00859642).
• BP6: Variant 12-6031493-C-T is Benign according to our data. Variant chr12-6031493-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100240.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1799/152226) while in subpopulation NFE AF = 0.0202 (1374/68008). AF 95% confidence interval is 0.0193. There are 13 homozygotes in GnomAd4. There are 816 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.2771G>A	p.Arg924Gln	missense	Exon 21 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.2771G>A	p.Arg924Gln	missense	Exon 21 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.2771G>A	p.Arg924Gln	missense	Exon 22 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2771G>A	p.Arg924Gln	missense	Exon 21 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1799 AN: 152108 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.00370

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.0105 AC: 2647 AN: 251494 AF XY: 0.0107

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0184 AC: 26843 AN: 1461870 Hom.: 284 Cov.: 31 AF XY: 0.0178 AC XY: 12950 AN XY: 727236

African (AFR) AF: 0.00293 AC: 98 AN: 33478

American (AMR) AF: 0.00425 AC: 190 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00329 AC: 86 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.00351 AC: 303 AN: 86254

European-Finnish (FIN) AF: 0.00620 AC: 331 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0224 AC: 24886 AN: 1111998

Other (OTH) AF: 0.0153 AC: 925 AN: 60396

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152226 Hom.: 13 Cov.: 31 AF XY: 0.0110 AC XY: 816 AN XY: 74448

African (AFR) AF: 0.00368 AC: 153 AN: 41526

American (AMR) AF: 0.0101 AC: 155 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1374 AN: 68008

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.0169 Hom.: 92

Bravo AF: 0.0112

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0106 AC: 1290

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0159

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (6)
-	1	2	von Willebrand disease type 2 (3)
-	1	1	von Willebrand disease type 1 (2)
-	-	2	von Willebrand disease type 3 (2)
-	1	-	Hereditary von Willebrand disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.51
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.089
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.023	B
Vest4		0.13
MPC		0.24
ClinPred		0.0062	T
GERP RS		3.8
Varity_R		0.088
gMVP		0.72
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs33978901; hg19: chr12-6140659; COSMIC: COSV99075173;