rs34444862

Variant names:

• chr12-5996230-G-C
• rs34444862
• NM_000552.5:c.5843-8C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-5996230-G-C
• chr12-5996230-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000552.5(VWF):​c.5843-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,606,738 control chromosomes in the GnomAD database, including 336 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.019 (321 hom.)
• Consequence: VWF NM_000552.5 splice_region, intron
• Scores: Splicing: ADA: 0.0004255
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.602
• Publications: 5 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-5996230-G-C is Benign according to our data. Variant chr12-5996230-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 619939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1882/152326) while in subpopulation NFE AF = 0.0214 (1454/68022). AF 95% confidence interval is 0.0205. There are 15 homozygotes in GnomAd4. There are 842 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

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.5843-8C>G		splice_region intron	N/A	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.5843-8C>G		splice_region intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.5843-8C>G		splice_region intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+33112C>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1883 AN: 152208 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.0114 AC: 2726 AN: 239088 AF XY: 0.0113

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00400

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00902

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0192 AC: 27869 AN: 1454412 Hom.: 321 Cov.: 34 AF XY: 0.0185 AC XY: 13376 AN XY: 722910

African (AFR) AF: 0.00327 AC: 109 AN: 33372

American (AMR) AF: 0.00459 AC: 201 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.00451 AC: 117 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00254 AC: 216 AN: 85044

European-Finnish (FIN) AF: 0.00924 AC: 490 AN: 53042

Middle Eastern (MID) AF: 0.00290 AC: 15 AN: 5174

European-Non Finnish (NFE) AF: 0.0232 AC: 25756 AN: 1108454

Other (OTH) AF: 0.0161 AC: 965 AN: 60084

GnomAD4 genome AF: 0.0124 AC: 1882 AN: 152326 Hom.: 15 Cov.: 32 AF XY: 0.0113 AC XY: 842 AN XY: 74508

African (AFR) AF: 0.00390 AC: 162 AN: 41574

American (AMR) AF: 0.00817 AC: 125 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1454 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.0157 Hom.: 7

Bravo AF: 0.0118

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Hereditary von Willebrand disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.30
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.020		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: rs34444862; hg19: chr12-6105396;