rs11063987

Variant names:

• chr12-6019114-T-C
• rs11063987
• NM_000552.5:c.4304A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP5 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000552.5:c.4304A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 1435. TThe Grpmax filtering allele frequency in gnomAD v4.1 is 0.1104 (based on 8427/74964 alleles in the African American population[, including 498 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. This variant has been observed in 1 patient with an alternate molecular basis for disease, the presence (with unreported phase) of the p.Arg1341Gln variant, previously classified Pathogenic by the ClinGen VWD Type 2 VCEP (BP5; PMID:30817071). At least 16 healthy adult individuals harboring the p.Asn1435Ser variant were found to be unaffected, with no diagnosis of a bleeding disorder and normal lab values, including bleeding scores lower than 4, VWF:RCo/VWF:Ag ratios >0.6, and no increased response to low-dose ristocetin (PMID:20231421). The mean VWF:RCo/VWF:Ag ratio of 0.71-0.77 within this group was significantly reduced compared to 0.91-0.97 for WT, but above the threshold of <0.6. However, BS2 was not considered due to incomplete penetrance in this gene-disease relationship. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402552/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.032 (272 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (238 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 1.84
• Publications: 10 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 -9 ACMG points.

• BP5: 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.4304A>G	p.Asn1435Ser	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.4304A>G	p.Asn1435Ser	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4304A>G	p.Asn1435Ser	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10228A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4809 AN: 152018 Hom.: 271 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.00818 AC: 2054 AN: 251132 AF XY: 0.00611

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00343 AC: 5017 AN: 1461662 Hom.: 238 Cov.: 98 AF XY: 0.00294 AC XY: 2141 AN XY: 727140

African (AFR) AF: 0.116 AC: 3890 AN: 33472

American (AMR) AF: 0.00539 AC: 241 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5762

European-Non Finnish (NFE) AF: 0.000351 AC: 390 AN: 1111832

Other (OTH) AF: 0.00732 AC: 442 AN: 60378

GnomAD4 genome AF: 0.0317 AC: 4817 AN: 152136 Hom.: 272 Cov.: 31 AF XY: 0.0308 AC XY: 2290 AN XY: 74378

African (AFR) AF: 0.109 AC: 4537 AN: 41492

American (AMR) AF: 0.0113 AC: 173 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68004

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.00765 Hom.: 41

Bravo AF: 0.0353

ESP6500AA AF: 0.103 AC: 454

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00988 AC: 1199

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	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 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.60
Sift	Benign	0.19	T
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.15
MVP		0.91
MPC		0.62
ClinPred		0.013	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.58
Mutation Taster		=89/11	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: rs11063987; hg19: chr12-6128280;