12-6065248-T-G

Variant names:

• chr12-6065248-T-G
• rs1800376
• NM_000552.5:c.1182A>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.1182A>C​(p.Ser394Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,308 control chromosomes in the GnomAD database, including 26,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6338 hom., cov: 33)
  • Exomes 𝑓: 0.15 (19692 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.113
• Publications: 12 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=-0.64).
• BP6: Variant 12-6065248-T-G is Benign according to our data. Variant chr12-6065248-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.113 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 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.1182A>C	p.Ser394Ser	synonymous	Exon 11 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.1182A>C	p.Ser394Ser	synonymous	Exon 11 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.420+45267A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35874 AN: 151742 Hom.: 6314 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.165 AC: 41315 AN: 250660 AF XY: 0.165

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.0861

Gnomad ASJ exome AF: 0.0916

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.150 AC: 218684 AN: 1461448 Hom.: 19692 Cov.: 34 AF XY: 0.152 AC XY: 110187 AN XY: 727012

African (AFR) AF: 0.502 AC: 16795 AN: 33464

American (AMR) AF: 0.0927 AC: 4145 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 2361 AN: 26130

East Asian (EAS) AF: 0.215 AC: 8530 AN: 39672

South Asian (SAS) AF: 0.240 AC: 20728 AN: 86190

European-Finnish (FIN) AF: 0.106 AC: 5654 AN: 53392

Middle Eastern (MID) AF: 0.177 AC: 1022 AN: 5762

European-Non Finnish (NFE) AF: 0.134 AC: 149229 AN: 1111760

Other (OTH) AF: 0.169 AC: 10220 AN: 60386

GnomAD4 genome AF: 0.237 AC: 35951 AN: 151860 Hom.: 6338 Cov.: 33 AF XY: 0.233 AC XY: 17288 AN XY: 74244

African (AFR) AF: 0.501 AC: 20680 AN: 41294

American (AMR) AF: 0.137 AC: 2088 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 262 AN: 3472

East Asian (EAS) AF: 0.222 AC: 1140 AN: 5146

South Asian (SAS) AF: 0.235 AC: 1130 AN: 4812

European-Finnish (FIN) AF: 0.103 AC: 1088 AN: 10570

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9041 AN: 67964

Other (OTH) AF: 0.195 AC: 411 AN: 2110

Alfa AF: 0.179 Hom.: 3340

Bravo AF: 0.250

Asia WGS AF: 0.245 AC: 850 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.132

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	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	-0.64
CADD	Benign	7.8
DANN	Benign	0.57
PhyloP100		0.11
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: rs1800376; hg19: chr12-6174414; COSMIC: COSV54629344;