rs1800375

Variant names:

• chr12-6065257-T-A
• rs1800375
• NM_000552.5:c.1173A>T

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.1173A>T​(p.Thr391Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,370 control chromosomes in the GnomAD database, including 24,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5793 hom., cov: 33)
  • Exomes 𝑓: 0.15 (19177 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.36
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-6065257-T-A is Benign according to our data. Variant chr12-6065257-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.467 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.1173A>T	p.Thr391Thr	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.1173A>T	p.Thr391Thr	synonymous	Exon 11 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.420+45258A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34627 AN: 151850 Hom.: 5777 Cov.: 33

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.133

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: 0.186

GnomAD2 exomes AF: 0.162 AC: 40630 AN: 250598 AF XY: 0.163

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.0840

Gnomad ASJ exome AF: 0.0914

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.149 AC: 217122 AN: 1461402 Hom.: 19177 Cov.: 34 AF XY: 0.151 AC XY: 109495 AN XY: 726974

African (AFR) AF: 0.475 AC: 15891 AN: 33462

American (AMR) AF: 0.0903 AC: 4037 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 2361 AN: 26134

East Asian (EAS) AF: 0.215 AC: 8520 AN: 39670

South Asian (SAS) AF: 0.240 AC: 20719 AN: 86200

European-Finnish (FIN) AF: 0.106 AC: 5646 AN: 53384

Middle Eastern (MID) AF: 0.175 AC: 1009 AN: 5764

European-Non Finnish (NFE) AF: 0.134 AC: 148873 AN: 1111712

Other (OTH) AF: 0.167 AC: 10066 AN: 60384

GnomAD4 genome AF: 0.228 AC: 34693 AN: 151968 Hom.: 5793 Cov.: 33 AF XY: 0.225 AC XY: 16708 AN XY: 74320

African (AFR) AF: 0.472 AC: 19522 AN: 41324

American (AMR) AF: 0.132 AC: 2023 AN: 15300

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

East Asian (EAS) AF: 0.221 AC: 1139 AN: 5154

South Asian (SAS) AF: 0.235 AC: 1134 AN: 4828

European-Finnish (FIN) AF: 0.103 AC: 1093 AN: 10596

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

European-Non Finnish (NFE) AF: 0.133 AC: 9017 AN: 67982

Other (OTH) AF: 0.186 AC: 392 AN: 2108

Alfa AF: 0.157 Hom.: 818

Bravo AF: 0.240

Asia WGS AF: 0.241 AC: 839 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.131

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	-0.85
CADD	Benign	2.5
DANN	Benign	0.26
PhyloP100		-2.4
Mutation Taster		=82/18	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: rs1800375; hg19: chr12-6174423; COSMIC: COSV54614898;