NM_000552.5:c.4414G>C

Variant names:

• chr12-6019004-C-G
• rs1800383
• NM_000552.5:c.4414G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000552.5(VWF):c.4414G>C (p.Asp1472His) is common in the general population with Grpmax filtering allele frequency of 0.5033 in gnomAD v4.1 (based on 38011/74882 alleles in the African/African American population). This is above the threshold of >0.1 (BA1). The computational predictor REVEL gives a score of 0.188, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI does not predict an impact to splicing with this variant. This variant does appear to impact laboratory values; the mean VWF:RCo/VWF:Ag ratio of 0.75-0.82 was significantly reduced compared to 0.91-0.97 for WT in 275 healthy adult individuals harboring the Asp1472His variant (PMID:20231421). In summary this variant meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402534/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.21 (5738 hom., cov: 31)
  • Exomes 𝑓: 0.10 (11370 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: -0.121
• Publications: 66 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.4414G>C	p.Asp1472His	missense	Exon 28 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.4414G>C	p.Asp1472His	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4414G>C	p.Asp1472His	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10338G>C		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31589 AN: 151844 Hom.: 5730 Cov.: 31

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.119 AC: 29448 AN: 248378 AF XY: 0.116

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.0733

Gnomad ASJ exome AF: 0.0597

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.0768

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.104 AC: 152489 AN: 1461350 Hom.: 11370 Cov.: 99 AF XY: 0.104 AC XY: 75805 AN XY: 726966

African (AFR) AF: 0.518 AC: 17322 AN: 33468

American (AMR) AF: 0.0798 AC: 3565 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 1521 AN: 26118

East Asian (EAS) AF: 0.108 AC: 4293 AN: 39682

South Asian (SAS) AF: 0.146 AC: 12554 AN: 86194

European-Finnish (FIN) AF: 0.0761 AC: 4063 AN: 53414

Middle Eastern (MID) AF: 0.119 AC: 684 AN: 5758

European-Non Finnish (NFE) AF: 0.0909 AC: 101083 AN: 1111674

Other (OTH) AF: 0.123 AC: 7404 AN: 60360

GnomAD4 genome AF: 0.208 AC: 31629 AN: 151962 Hom.: 5738 Cov.: 31 AF XY: 0.205 AC XY: 15247 AN XY: 74276

African (AFR) AF: 0.500 AC: 20689 AN: 41414

American (AMR) AF: 0.127 AC: 1940 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3470

East Asian (EAS) AF: 0.115 AC: 592 AN: 5136

South Asian (SAS) AF: 0.148 AC: 711 AN: 4806

European-Finnish (FIN) AF: 0.0760 AC: 805 AN: 10590

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0903 AC: 6139 AN: 67956

Other (OTH) AF: 0.205 AC: 432 AN: 2108

Alfa AF: 0.0764 Hom.: 238

Bravo AF: 0.226

TwinsUK AF: 0.0882 AC: 327

ALSPAC AF: 0.0877 AC: 338

ESP6500AA AF: 0.393 AC: 1717

ESP6500EA AF: 0.0657 AC: 565

ExAC AF: 0.129 AC: 15584

EpiCase AF: 0.0910

EpiControl AF: 0.0912

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.083
DANN	Benign	0.22
DEOGEN2	Benign	0.27	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.000024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.12
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.32
ClinPred		0.0065	T
GERP RS		0.81
Varity_R		0.032
gMVP		0.49
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800383; hg19: chr12-6128170; COSMIC: COSV54620580; COSMIC: COSV54620580;