rs216311

Variant names:

• chr12-6019277-T-C
• rs216311
• NM_000552.5:c.4141A>G
• VWF p.Thr1381Ala

Your query was ambiguous. Multiple possible variants found:

• chr12-6019277-T-C
• chr12-6019277-T-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP5 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000552.5(VWF):c.4141A>G (p.Thr1381Ala) is common in the general population with a Grpmax filtering allele frequency of 0.8925 (based on 67313/74942 alleles in the African/African American population) in gnomAD v4.1 (BA1). Several probands have been reported (PMID:30817071, PMID:30762591) with Thr1381Ala in cis or trans with additional vWF variants, including the type 2B Arg1308Cys variant (ClinVar 289, classified Pathogenic by the ClinGen VWD VCEP; BP5). and therefore meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4, BP5 (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; 08/12/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402593/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.72 (39998 hom., cov: 30)
  • Exomes 𝑓: 0.64 (301018 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: 1.88
• Publications: 54 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: Orphanet, ClinGen
• 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.4141A>G	p.Thr1381Ala	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.4141A>G	p.Thr1381Ala	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4141A>G	p.Thr1381Ala	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10065A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108580 AN: 151844 Hom.: 39958 Cov.: 30

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.753

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.724

GnomAD2 exomes AF: 0.686 AC: 170206 AN: 248236 AF XY: 0.681

Gnomad AFR exome AF: 0.897

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.762

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.638 AC: 931862 AN: 1461560 Hom.: 301018 Cov.: 84 AF XY: 0.640 AC XY: 465156 AN XY: 727084

African (AFR) AF: 0.905 AC: 30285 AN: 33472

American (AMR) AF: 0.802 AC: 35882 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 17889 AN: 26132

East Asian (EAS) AF: 0.738 AC: 29289 AN: 39700

South Asian (SAS) AF: 0.743 AC: 64124 AN: 86250

European-Finnish (FIN) AF: 0.551 AC: 29395 AN: 53390

Middle Eastern (MID) AF: 0.765 AC: 4410 AN: 5762

European-Non Finnish (NFE) AF: 0.612 AC: 680452 AN: 1111764

Other (OTH) AF: 0.665 AC: 40136 AN: 60374

GnomAD4 genome AF: 0.715 AC: 108674 AN: 151962 Hom.: 39998 Cov.: 30 AF XY: 0.717 AC XY: 53254 AN XY: 74240

African (AFR) AF: 0.893 AC: 37028 AN: 41470

American (AMR) AF: 0.754 AC: 11512 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2373 AN: 3468

East Asian (EAS) AF: 0.747 AC: 3841 AN: 5142

South Asian (SAS) AF: 0.766 AC: 3680 AN: 4806

European-Finnish (FIN) AF: 0.549 AC: 5788 AN: 10536

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42073 AN: 67946

Other (OTH) AF: 0.720 AC: 1520 AN: 2110

Alfa AF: 0.658 Hom.: 27088

Bravo AF: 0.739

Asia WGS AF: 0.772 AC: 2686 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	4	not specified (4)
-	-	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	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.14
DANN	Benign	0.18
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0000053	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.1	N
PhyloP100		1.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.11
gMVP		0.56
Mutation Taster		=91/9	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs216311;

hg19: chr12-6128443;

COSMIC: COSV104372976;

COSMIC: COSV104372976;