chr12-6018777-A-G

Variant names:

• chr12-6018777-A-G
• rs216310
• NM_000552.5:c.4641T>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.4641T>C​(p.Thr1547Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,601,608 control chromosomes in the GnomAD database, including 341,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39994 hom., cov: 30)
  • Exomes 𝑓: 0.64 (301545 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: -1.16
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 12-6018777-A-G is Benign according to our data. Variant chr12-6018777-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 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.4641T>C	p.Thr1547Thr	synonymous	Exon 28 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.4641T>C	p.Thr1547Thr	synonymous	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4641T>C	p.Thr1547Thr	synonymous	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10565T>C		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108540 AN: 151694 Hom.: 39958 Cov.: 30

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.753

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.723

GnomAD2 exomes AF: 0.689 AC: 169960 AN: 246712 AF XY: 0.685

Gnomad AFR exome AF: 0.902

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.687

Gnomad EAS exome AF: 0.764

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.639 AC: 926963 AN: 1449796 Hom.: 301545 Cov.: 62 AF XY: 0.642 AC XY: 462459 AN XY: 720526

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.905 AC: 30213 AN: 33374

American (AMR) AF: 0.802 AC: 35595 AN: 44364

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 17937 AN: 26042

East Asian (EAS) AF: 0.738 AC: 29160 AN: 39486

South Asian (SAS) AF: 0.751 AC: 64474 AN: 85908

European-Finnish (FIN) AF: 0.547 AC: 28948 AN: 52938

Middle Eastern (MID) AF: 0.771 AC: 4386 AN: 5692

European-Non Finnish (NFE) AF: 0.614 AC: 676290 AN: 1102060

Other (OTH) AF: 0.667 AC: 39960 AN: 59932

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.716 AC: 108630 AN: 151812 Hom.: 39994 Cov.: 30 AF XY: 0.718 AC XY: 53229 AN XY: 74160

African (AFR) AF: 0.892 AC: 36958 AN: 41414

American (AMR) AF: 0.753 AC: 11493 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2390 AN: 3468

East Asian (EAS) AF: 0.748 AC: 3840 AN: 5136

South Asian (SAS) AF: 0.773 AC: 3712 AN: 4800

European-Finnish (FIN) AF: 0.546 AC: 5752 AN: 10544

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.620 AC: 42113 AN: 67872

Other (OTH) AF: 0.719 AC: 1518 AN: 2110

Alfa AF: 0.647 Hom.: 9534

Bravo AF: 0.739

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	4	not specified (4)
-	-	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
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.071
DANN	Benign	0.28
PhyloP100		-1.2
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: rs216310; hg19: chr12-6127943; COSMIC: COSV54625202; COSMIC: COSV54625202;