rs216312

Variant names:

• chr12-6019818-T-C
• rs216312
• NM_000552.5:c.3675-75A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.3675-75A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,486,220 control chromosomes in the GnomAD database, including 243,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30433 hom., cov: 32)
  • Exomes 𝑓: 0.56 (212972 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.100
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 12-6019818-T-C is Benign according to our data. Variant chr12-6019818-T-C is described in ClinVar as Benign. ClinVar VariationId is 1241069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 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.3675-75A>G		intron	N/A	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3675-75A>G		intron	N/A	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-25884A>G		intron	N/A
	VWF	ENST00000539641.1	TSL:3	n.473-75A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94775 AN: 151912 Hom.: 30387 Cov.: 32

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.634

GnomAD4 exome AF: 0.562 AC: 750239 AN: 1334190 Hom.: 212972 AF XY: 0.562 AC XY: 372277 AN XY: 662154

African (AFR) AF: 0.773 AC: 23839 AN: 30828

American (AMR) AF: 0.728 AC: 25981 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 15843 AN: 24828

East Asian (EAS) AF: 0.625 AC: 22600 AN: 36138

South Asian (SAS) AF: 0.585 AC: 45608 AN: 77976

European-Finnish (FIN) AF: 0.477 AC: 18649 AN: 39068

Middle Eastern (MID) AF: 0.669 AC: 2767 AN: 4138

European-Non Finnish (NFE) AF: 0.546 AC: 562213 AN: 1029556

Other (OTH) AF: 0.585 AC: 32739 AN: 55980

GnomAD4 genome AF: 0.624 AC: 94876 AN: 152030 Hom.: 30433 Cov.: 32 AF XY: 0.624 AC XY: 46340 AN XY: 74310

African (AFR) AF: 0.763 AC: 31631 AN: 41462

American (AMR) AF: 0.683 AC: 10434 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2233 AN: 3472

East Asian (EAS) AF: 0.631 AC: 3259 AN: 5162

South Asian (SAS) AF: 0.599 AC: 2882 AN: 4810

European-Finnish (FIN) AF: 0.473 AC: 5000 AN: 10580

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37325 AN: 67944

Other (OTH) AF: 0.632 AC: 1334 AN: 2112

Alfa AF: 0.579 Hom.: 55668

Bravo AF: 0.648

Asia WGS AF: 0.650 AC: 2258 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.7
DANN	Benign	0.43
PhyloP100		0.10
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: rs216312; hg19: chr12-6128984;