12-5993928-C-A

Variant names:

• chr12-5993928-C-A
• rs34230288
• NM_000552.5:c.6532G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000552.5(VWF):​c.6532G>T​(p.Ala2178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,996 control chromosomes in the GnomAD database, including 339 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2178V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 31)
  • Exomes 𝑓: 0.019 (325 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0150
• Publications: 14 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 -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000552.5
• 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=0.008763671).
• BP6: Variant 12-5993928-C-A is Benign according to our data. Variant chr12-5993928-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 619942.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0125 (1896/152182) while in subpopulation NFE AF = 0.0215 (1462/68006). AF 95% confidence interval is 0.0206. There are 14 homozygotes in GnomAd4. There are 848 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

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.6532G>T	p.Ala2178Ser	missense	Exon 37 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.6532G>T	p.Ala2178Ser	missense	Exon 37 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.427G>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1897 AN: 152064 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0113 AC: 2825 AN: 251010 AF XY: 0.0112

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00899

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0192 AC: 28029 AN: 1461814 Hom.: 325 Cov.: 32 AF XY: 0.0185 AC XY: 13463 AN XY: 727196

African (AFR) AF: 0.00329 AC: 110 AN: 33480

American (AMR) AF: 0.00454 AC: 203 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00448 AC: 117 AN: 26136

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

South Asian (SAS) AF: 0.00255 AC: 220 AN: 86256

European-Finnish (FIN) AF: 0.00928 AC: 495 AN: 53352

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0233 AC: 25894 AN: 1112002

Other (OTH) AF: 0.0161 AC: 974 AN: 60396

GnomAD4 genome AF: 0.0125 AC: 1896 AN: 152182 Hom.: 14 Cov.: 31 AF XY: 0.0114 AC XY: 848 AN XY: 74390

African (AFR) AF: 0.00402 AC: 167 AN: 41520

American (AMR) AF: 0.00818 AC: 125 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4812

European-Finnish (FIN) AF: 0.00726 AC: 77 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1462 AN: 68006

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.0173 Hom.: 119

Bravo AF: 0.0118

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0226 AC: 194

ExAC AF: 0.0113 AC: 1372

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0197

EpiControl AF: 0.0167

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.6
DANN	Benign	0.80
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.015
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.12
Sift	Benign	0.58	T
Sift4G	Benign	0.91	T
Polyphen		0.0020	B
Vest4		0.081
MPC		0.25
ClinPred		0.00058	T
GERP RS		-0.72
Varity_R		0.067
gMVP		0.37
Mutation Taster		=95/5	polymorphism

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: rs34230288; hg19: chr12-6103094; COSMIC: COSV99075171;