rs144072210

Variant names:

• chr12-5996214-T-C
• rs144072210
• NM_000552.5:c.5851A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_000552.5(VWF):​c.5851A>G​(p.Thr1951Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,611,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10
• Conservation: PhyloP100: 3.27
• Publications: 4 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: Likely_benign. The variant received -3 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=0.04290828).

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.5851A>G	p.Thr1951Ala	missense	Exon 35 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.5851A>G	p.Thr1951Ala	missense	Exon 35 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.5851A>G	p.Thr1951Ala	missense	Exon 36 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+33128A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000558 AC: 138 AN: 247230 AF XY: 0.000547

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000839

Gnomad NFE exome AF: 0.000886

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000428 AC: 624 AN: 1459526 Hom.: 1 Cov.: 32 AF XY: 0.000433 AC XY: 314 AN XY: 725884

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.0000450 AC: 2 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 45 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85780

European-Finnish (FIN) AF: 0.000713 AC: 38 AN: 53324

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5448

European-Non Finnish (NFE) AF: 0.000462 AC: 513 AN: 1111072

Other (OTH) AF: 0.000398 AC: 24 AN: 60294

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74354

African (AFR) AF: 0.0000724 AC: 3 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000831 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000618 AC: 75

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	von Willebrand disease type 1 (2)
1	-	-	Abnormality of coagulation (1)
-	1	-	Hereditary von Willebrand disease (1)
-	1	-	not specified (1)
-	1	-	von Willebrand disease type 1;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	0.093
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.047	B
Vest4		0.13
MVP		0.54
MPC		0.83
ClinPred		0.020	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.62
Mutation Taster		=23/77	disease causing (ClinVar)

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: rs144072210; hg19: chr12-6105380;