rs1063856

Variant names:

• chr12-6044368-T-C
• rs1063856
• NM_000552.5:c.2365A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-6044368-T-C
• chr12-6044368-T-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.2365A>G​(p.Thr789Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,858 control chromosomes in the GnomAD database, including 107,997 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T789P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13217 hom., cov: 33)
  • Exomes 𝑓: 0.35 (94780 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 0.942
• Publications: 113 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 -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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=6.430792E-5).
• BP6: Variant 12-6044368-T-C is Benign according to our data. Variant chr12-6044368-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

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.2365A>G	p.Thr789Ala	missense	Exon 18 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.2365A>G	p.Thr789Ala	missense	Exon 18 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.2365A>G	p.Thr789Ala	missense	Exon 19 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2365A>G	p.Thr789Ala	missense	Exon 18 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60042 AN: 151930 Hom.: 13190 Cov.: 33

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.372

GnomAD2 exomes AF: 0.312 AC: 78459 AN: 251226 AF XY: 0.311

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.0702

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.352 AC: 514079 AN: 1461810 Hom.: 94780 Cov.: 59 AF XY: 0.348 AC XY: 253379 AN XY: 727206

African (AFR) AF: 0.583 AC: 19524 AN: 33480

American (AMR) AF: 0.190 AC: 8476 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7687 AN: 26134

East Asian (EAS) AF: 0.0709 AC: 2813 AN: 39700

South Asian (SAS) AF: 0.249 AC: 21484 AN: 86252

European-Finnish (FIN) AF: 0.358 AC: 19112 AN: 53402

Middle Eastern (MID) AF: 0.282 AC: 1627 AN: 5766

European-Non Finnish (NFE) AF: 0.371 AC: 412171 AN: 1111968

Other (OTH) AF: 0.351 AC: 21185 AN: 60386

GnomAD4 genome AF: 0.395 AC: 60108 AN: 152048 Hom.: 13217 Cov.: 33 AF XY: 0.387 AC XY: 28788 AN XY: 74336

African (AFR) AF: 0.576 AC: 23885 AN: 41448

American (AMR) AF: 0.269 AC: 4115 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1022 AN: 3462

East Asian (EAS) AF: 0.0774 AC: 400 AN: 5170

South Asian (SAS) AF: 0.236 AC: 1137 AN: 4816

European-Finnish (FIN) AF: 0.354 AC: 3739 AN: 10576

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24605 AN: 67964

Other (OTH) AF: 0.368 AC: 779 AN: 2116

Alfa AF: 0.365 Hom.: 33481

Bravo AF: 0.400

TwinsUK AF: 0.370 AC: 1372

ALSPAC AF: 0.377 AC: 1453

ESP6500AA AF: 0.568 AC: 2504

ESP6500EA AF: 0.357 AC: 3074

ExAC AF: 0.323 AC: 39189

Asia WGS AF: 0.204 AC: 710 AN: 3478

EpiCase AF: 0.354

EpiControl AF: 0.362

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	not specified (3)
-	-	1	Hereditary von Willebrand disease (1)
-	-	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	0.049
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.000064	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.94
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.048
MPC		0.18
ClinPred		0.00037	T
GERP RS		2.2
Varity_R		0.17
gMVP		0.55
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: rs1063856; hg19: chr12-6153534; COSMIC: COSV54612011;