12-6034818-T-C

Variant names:

• chr12-6034818-T-C
• rs216321
• NM_000552.5:c.2555A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BA1

The NM_000552.5(VWF):​c.2555A>G​(p.Gln852Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 1,614,050 control chromosomes in the GnomAD database, including 662,737 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q852E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.92 (64098 hom., cov: 33)
  • Exomes 𝑓: 0.90 (598639 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.552
• Publications: 59 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 type 2B

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000552.5
• 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=5.94502E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.2555A>G	p.Gln852Arg	missense	Exon 20 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.2555A>G	p.Gln852Arg	missense	Exon 20 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-40884A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.917 AC: 139460 AN: 152158 Hom.: 64045 Cov.: 33

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.922

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.917

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.924

GnomAD2 exomes AF: 0.900 AC: 226185 AN: 251332 AF XY: 0.898

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.917

Gnomad ASJ exome AF: 0.945

Gnomad EAS exome AF: 0.794

Gnomad FIN exome AF: 0.895

Gnomad NFE exome AF: 0.908

Gnomad OTH exome AF: 0.909

GnomAD4 exome AF: 0.905 AC: 1322288 AN: 1461774 Hom.: 598639 Cov.: 69 AF XY: 0.903 AC XY: 656815 AN XY: 727168

African (AFR) AF: 0.954 AC: 31945 AN: 33476

American (AMR) AF: 0.916 AC: 40966 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 24700 AN: 26136

East Asian (EAS) AF: 0.795 AC: 31553 AN: 39694

South Asian (SAS) AF: 0.869 AC: 74934 AN: 86248

European-Finnish (FIN) AF: 0.888 AC: 47455 AN: 53418

Middle Eastern (MID) AF: 0.922 AC: 5318 AN: 5768

European-Non Finnish (NFE) AF: 0.909 AC: 1010614 AN: 1111926

Other (OTH) AF: 0.908 AC: 54803 AN: 60388

GnomAD4 genome AF: 0.917 AC: 139570 AN: 152276 Hom.: 64098 Cov.: 33 AF XY: 0.915 AC XY: 68148 AN XY: 74446

African (AFR) AF: 0.951 AC: 39517 AN: 41558

American (AMR) AF: 0.922 AC: 14110 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 3266 AN: 3472

East Asian (EAS) AF: 0.792 AC: 4098 AN: 5174

South Asian (SAS) AF: 0.877 AC: 4226 AN: 4818

European-Finnish (FIN) AF: 0.897 AC: 9518 AN: 10610

Middle Eastern (MID) AF: 0.921 AC: 269 AN: 292

European-Non Finnish (NFE) AF: 0.908 AC: 61784 AN: 68022

Other (OTH) AF: 0.919 AC: 1940 AN: 2112

Alfa AF: 0.910 Hom.: 289495

Bravo AF: 0.921

ESP6500AA AF: 0.950 AC: 4184

ESP6500EA AF: 0.911 AC: 7832

ExAC AF: 0.899 AC: 109150

Asia WGS AF: 0.840 AC: 2924 AN: 3478

EpiCase AF: 0.914

EpiControl AF: 0.918

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.9
DANN	Benign	0.54
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.010	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.42	N
PhyloP100		-0.55
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.086
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.20
ClinPred		0.00065	T
GERP RS		0.42
Varity_R		0.045
gMVP		0.38
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: rs216321; hg19: chr12-6143984; COSMIC: COSV54629324;