rs1800377

Variant names:

• chr12-6064267-C-T
• rs1800377
• NM_000552.5:c.1411G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:8
• Conservation: PhyloP100: 0.00400
• Publications: 26 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 -19 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=0.0015455186).
• BP6: Variant 12-6064267-C-T is Benign according to our data. Variant chr12-6064267-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

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.1411G>A	p.Val471Ile	missense	Exon 12 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.1411G>A	p.Val471Ile	missense	Exon 12 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.1411G>A	p.Val471Ile	missense	Exon 13 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.1411G>A	p.Val471Ile	missense	Exon 12 of 27	ENSP00000565739.1

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

GnomAD2 exomes AF: 0.114 AC: 28579 AN: 250654 AF XY: 0.118

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 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

African (AFR) AF: 0.132 AC: 4431 AN: 33480

American (AMR) AF: 0.0501 AC: 2242 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 1281 AN: 26134

East Asian (EAS) AF: 0.163 AC: 6463 AN: 39698

South Asian (SAS) AF: 0.175 AC: 15062 AN: 86256

European-Finnish (FIN) AF: 0.0995 AC: 5306 AN: 53352

Middle Eastern (MID) AF: 0.0970 AC: 559 AN: 5762

European-Non Finnish (NFE) AF: 0.116 AC: 128862 AN: 1111980

Other (OTH) AF: 0.116 AC: 7016 AN: 60396

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

African (AFR) AF: 0.139 AC: 5758 AN: 41550

American (AMR) AF: 0.0623 AC: 953 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3468

East Asian (EAS) AF: 0.169 AC: 873 AN: 5168

South Asian (SAS) AF: 0.176 AC: 849 AN: 4820

European-Finnish (FIN) AF: 0.0930 AC: 987 AN: 10610

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7754 AN: 68018

Other (OTH) AF: 0.0908 AC: 192 AN: 2114

Alfa AF: 0.114 Hom.: 3360

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.0040
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
Mutation Taster		=95/5	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: rs1800377; hg19: chr12-6173433; COSMIC: COSV107218037;