chr7-12333513-A-C

Variant names:

• chr7-12333513-A-C
• rs201760075
• NM_001135924.3:c.4710T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001135924.3(VWDE):​c.4710T>G​(p.Cys1570Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,551,310 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.169
• Publications: 5 publications found

Genes affected

VWDE (HGNC:21897): (von Willebrand factor D and EGF domains) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135924.3. 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
	VWDE	NM_001135924.3	MANE Select	c.4710T>G	p.Cys1570Trp	missense	Exon 28 of 29	NP_001129396.1	Q8N2E2-1
	VWDE	NM_001346972.2		c.4365T>G	p.Cys1455Trp	missense	Exon 26 of 27	NP_001333901.1
	VWDE	NM_001346973.2		c.3900T>G	p.Cys1300Trp	missense	Exon 26 of 27	NP_001333902.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWDE	ENST00000275358.8	TSL:5 MANE Select	c.4710T>G	p.Cys1570Trp	missense	Exon 28 of 29	ENSP00000275358.3	Q8N2E2-1
	VWDE	ENST00000452576.6	TSL:1	n.*1474T>G		non_coding_transcript_exon	Exon 29 of 30	ENSP00000401687.2	J3KQJ9
	VWDE	ENST00000452576.6	TSL:1	n.*1474T>G		3_prime_UTR	Exon 29 of 30	ENSP00000401687.2	J3KQJ9

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00107 AC: 168 AN: 156446 AF XY: 0.00107

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.000685

GnomAD4 exome AF: 0.00137 AC: 1920 AN: 1398988 Hom.: 2 Cov.: 30 AF XY: 0.00133 AC XY: 915 AN XY: 690014

African (AFR) AF: 0.000158 AC: 5 AN: 31586

American (AMR) AF: 0.000504 AC: 18 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.000215 AC: 17 AN: 79216

European-Finnish (FIN) AF: 0.00241 AC: 119 AN: 49278

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5694

European-Non Finnish (NFE) AF: 0.00158 AC: 1704 AN: 1078680

Other (OTH) AF: 0.000966 AC: 56 AN: 57978

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74478

African (AFR) AF: 0.000337 AC: 14 AN: 41590

American (AMR) AF: 0.000458 AC: 7 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00151 AC: 103 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.000729

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 8

ExAC AF: 0.000651 AC: 16

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	0.00083	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		0.17
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.80
ClinPred		0.22	T
GERP RS		1.2
Varity_R		0.86
gMVP		0.97
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201760075; hg19: chr7-12373139;