12-6073662-A-T

Variant names:

• chr12-6073662-A-T
• rs1800387
• NM_000552.5:c.954T>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.954T>A​(p.Asn318Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,613,830 control chromosomes in the GnomAD database, including 8,471 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N318S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (3887 hom., cov: 31)
  • Exomes 𝑓: 0.041 (4584 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.129
• Publications: 19 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 -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=0.003455609).
• BP6: Variant 12-6073662-A-T is Benign according to our data. Variant chr12-6073662-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 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.954T>A	p.Asn318Lys	missense	Exon 8 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.954T>A	p.Asn318Lys	missense	Exon 8 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.420+36853T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21782 AN: 151860 Hom.: 3879 Cov.: 31

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.0612 AC: 15377 AN: 251422 AF XY: 0.0564

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.0391

Gnomad ASJ exome AF: 0.0562

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0511

GnomAD4 exome AF: 0.0414 AC: 60463 AN: 1461852 Hom.: 4584 Cov.: 32 AF XY: 0.0416 AC XY: 30246 AN XY: 727230

African (AFR) AF: 0.447 AC: 14966 AN: 33480

American (AMR) AF: 0.0445 AC: 1991 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 1498 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0789 AC: 6809 AN: 86258

European-Finnish (FIN) AF: 0.0185 AC: 987 AN: 53380

Middle Eastern (MID) AF: 0.0919 AC: 530 AN: 5768

European-Non Finnish (NFE) AF: 0.0271 AC: 30171 AN: 1112012

Other (OTH) AF: 0.0579 AC: 3497 AN: 60396

GnomAD4 genome AF: 0.144 AC: 21820 AN: 151978 Hom.: 3887 Cov.: 31 AF XY: 0.140 AC XY: 10402 AN XY: 74304

African (AFR) AF: 0.426 AC: 17628 AN: 41350

American (AMR) AF: 0.0794 AC: 1214 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

South Asian (SAS) AF: 0.0637 AC: 307 AN: 4816

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0295 AC: 2005 AN: 67966

Other (OTH) AF: 0.118 AC: 247 AN: 2100

Alfa AF: 0.0467 Hom.: 460

Bravo AF: 0.161

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.412 AC: 1814

ESP6500EA AF: 0.0258 AC: 222

ExAC AF: 0.0690 AC: 8382

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.0321

EpiControl AF: 0.0335

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hereditary von Willebrand disease (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	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.13
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.26
Sift	Benign	0.24	T
Sift4G	Benign	0.27	T
Polyphen		0.77	P
Vest4		0.082
MutPred		0.58		Gain of methylation at N318 (P = 0.0037)
MPC		0.31
ClinPred		0.0048	T
GERP RS		-3.5
Varity_R		0.13
gMVP		0.36
Mutation Taster		=71/29	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: rs1800387; hg19: chr12-6182828;