12-6036483-A-T

Variant names:

• chr12-6036483-A-T
• rs57950734
• NM_000552.5:c.2451T>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.2451T>A​(p.His817Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,613,052 control chromosomes in the GnomAD database, including 488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (258 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (230 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.251
• Publications: 20 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 -17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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=0.0040214956).
• BP6: Variant 12-6036483-A-T is Benign according to our data. Variant chr12-6036483-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 100224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 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.2451T>A	p.His817Gln	missense	Exon 19 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.2451T>A	p.His817Gln	missense	Exon 19 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.2451T>A	p.His817Gln	missense	Exon 20 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2451T>A	p.His817Gln	missense	Exon 19 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5050 AN: 152158 Hom.: 258 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.00871 AC: 2189 AN: 251434 AF XY: 0.00616

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00625

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00323 AC: 4711 AN: 1460776 Hom.: 230 Cov.: 33 AF XY: 0.00277 AC XY: 2016 AN XY: 726742

African (AFR) AF: 0.115 AC: 3842 AN: 33462

American (AMR) AF: 0.00705 AC: 315 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5754

European-Non Finnish (NFE) AF: 0.000118 AC: 131 AN: 1111116

Other (OTH) AF: 0.00650 AC: 392 AN: 60350

GnomAD4 genome AF: 0.0332 AC: 5063 AN: 152276 Hom.: 258 Cov.: 33 AF XY: 0.0322 AC XY: 2396 AN XY: 74456

African (AFR) AF: 0.115 AC: 4784 AN: 41554

American (AMR) AF: 0.0135 AC: 206 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68008

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.00504 Hom.: 30

Bravo AF: 0.0378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.117 AC: 514

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0109 AC: 1325

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	2	Hereditary von Willebrand disease (2)
-	-	1	not specified (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (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	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.25
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.21	B
Vest4		0.15
MutPred		0.54		Gain of catalytic residue at G813 (P = 0.0084)
MPC		0.57
ClinPred		0.027	T
GERP RS		-0.031
Varity_R		0.37
gMVP		0.78
Mutation Taster		=86/14	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: rs57950734; hg19: chr12-6145649; COSMIC: COSV105844008;