12-5981834-A-G

Variant names:

• chr12-5981834-A-G
• rs216867
• NM_000552.5:c.7239T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):​c.7239T>C​(p.Thr2413Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 1,613,984 control chromosomes in the GnomAD database, including 619,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (54712 hom., cov: 31)
  • Exomes 𝑓: 0.88 (564606 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.398
• Publications: 25 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-5981834-A-G is Benign according to our data. Variant chr12-5981834-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.398 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.7239T>C	p.Thr2413Thr	synonymous	Exon 42 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.7239T>C	p.Thr2413Thr	synonymous	Exon 42 of 52	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.845 AC: 128523 AN: 152026 Hom.: 54671 Cov.: 31

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.885

Gnomad OTH AF: 0.858

GnomAD2 exomes AF: 0.874 AC: 219875 AN: 251444 AF XY: 0.871

Gnomad AFR exome AF: 0.733

Gnomad AMR exome AF: 0.935

Gnomad ASJ exome AF: 0.899

Gnomad EAS exome AF: 0.926

Gnomad FIN exome AF: 0.894

Gnomad NFE exome AF: 0.882

Gnomad OTH exome AF: 0.876

GnomAD4 exome AF: 0.878 AC: 1283401 AN: 1461840 Hom.: 564606 Cov.: 73 AF XY: 0.876 AC XY: 636862 AN XY: 727218

African (AFR) AF: 0.722 AC: 24152 AN: 33474

American (AMR) AF: 0.930 AC: 41587 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 23461 AN: 26136

East Asian (EAS) AF: 0.949 AC: 37666 AN: 39700

South Asian (SAS) AF: 0.799 AC: 68928 AN: 86256

European-Finnish (FIN) AF: 0.896 AC: 47828 AN: 53398

Middle Eastern (MID) AF: 0.811 AC: 4678 AN: 5768

European-Non Finnish (NFE) AF: 0.884 AC: 982674 AN: 1111988

Other (OTH) AF: 0.868 AC: 52427 AN: 60396

GnomAD4 genome AF: 0.845 AC: 128617 AN: 152144 Hom.: 54712 Cov.: 31 AF XY: 0.846 AC XY: 62903 AN XY: 74390

African (AFR) AF: 0.738 AC: 30614 AN: 41462

American (AMR) AF: 0.894 AC: 13674 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3136 AN: 3470

East Asian (EAS) AF: 0.924 AC: 4768 AN: 5162

South Asian (SAS) AF: 0.797 AC: 3832 AN: 4808

European-Finnish (FIN) AF: 0.899 AC: 9526 AN: 10602

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.885 AC: 60208 AN: 68022

Other (OTH) AF: 0.858 AC: 1814 AN: 2114

Alfa AF: 0.876 Hom.: 132983

Bravo AF: 0.843

Asia WGS AF: 0.851 AC: 2960 AN: 3478

EpiCase AF: 0.880

EpiControl AF: 0.881

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary von Willebrand disease (1)
-	-	1	not provided (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
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.61
DANN	Benign	0.60
PhyloP100		-0.40
Mutation Taster		=100/0	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: rs216867; hg19: chr12-6091000; COSMIC: COSV99778494;