12-6019726-T-C

Variant names:

• chr12-6019726-T-C
• rs61749368
• NM_000552.5:c.3692A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6 BS1 BS2_Supporting

The NM_000552.5(VWF):​c.3692A>G​(p.Asn1231Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,612,190 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1231T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (10 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 3.00
• Publications: 17 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 -9 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=0.009687215).
• BP6: Variant 12-6019726-T-C is Benign according to our data. Variant chr12-6019726-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 976752.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000493 (75/152208) while in subpopulation SAS AF = 0.0112 (54/4810). AF 95% confidence interval is 0.00884. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3692A>G	p.Asn1231Ser	missense	Exon 28 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.3692A>G	p.Asn1231Ser	missense	Exon 28 of 52	ENSP00000261405.5
	VWF	ENST00000895679.1		c.3692A>G	p.Asn1231Ser	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9616A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 152090 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00144 AC: 350 AN: 242782 AF XY: 0.00187

Gnomad AFR exome AF: 0.0000682

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000315

Gnomad OTH exome AF: 0.000838

GnomAD4 exome AF: 0.000789 AC: 1152 AN: 1459982 Hom.: 10 Cov.: 38 AF XY: 0.00104 AC XY: 756 AN XY: 726258

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.000270 AC: 12 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.00960 AC: 826 AN: 86074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5730

European-Non Finnish (NFE) AF: 0.000226 AC: 251 AN: 1110876

Other (OTH) AF: 0.000813 AC: 49 AN: 60294

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74442

African (AFR) AF: 0.00 AC: 0 AN: 41528

American (AMR) AF: 0.000392 AC: 6 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00145 AC: 176

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	not specified (2)
-	1	-	Hereditary von Willebrand disease (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 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.020
Sift	Benign	0.17	T
Sift4G	Benign	0.29	T
Polyphen		0.0070	B
Vest4		0.21
MVP		0.32
MPC		0.25
ClinPred		0.011	T
GERP RS		2.6
Varity_R		0.20
gMVP		0.43
Mutation Taster		=85/15	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: rs61749368; hg19: chr12-6128892; COSMIC: COSV105844005;