7-12356207-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135924.3(VWDE):c.3649G>T(p.Val1217Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.975

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092179954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.3649G>T	p.Val1217Leu	missense_variant	18/29	ENST00000275358.8
VWDE	NM_001346972.2	c.3304G>T	p.Val1102Leu	missense_variant	16/27
VWDE	NM_001346973.2	c.2839G>T	p.Val947Leu	missense_variant	16/27
VWDE	NR_144534.2	n.3798G>T		non_coding_transcript_exon_variant	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.3649G>T	p.Val1217Leu	missense_variant	18/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.3649G>T	p.Val1217Leu	missense_variant, NMD_transcript_variant	18/30	1
VWDE	ENST00000644150.1	c.124G>T	p.Val42Leu	missense_variant	1/3
VWDE	ENST00000521169.5	c.*2027G>T		3_prime_UTR_variant, NMD_transcript_variant	15/26	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000639 AC: 1 AN: 156538 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82972

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000918

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399364 Hom.: 0 Cov.: 35 AF XY: 0.00000290 AC XY: 2 AN XY: 690188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000839

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.3649G>T (p.V1217L) alteration is located in exon 18 (coding exon 18) of the VWDE gene. This alteration results from a G to T substitution at nucleotide position 3649, causing the valine (V) at amino acid position 1217 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	2.1
Dann	Benign	0.92
DEOGEN2	Benign	0.022	T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.82	T;D;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;.;.
REVEL	Benign	0.044
Sift	Benign	0.15	T;.;.
Sift4G	Benign	0.29	T;T;.
Polyphen		0.50	P;.;.
Vest4		0.14
MutPred		0.29		Loss of stability (P = 0.1433);.;.;
MVP		0.048
ClinPred		0.066	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs1273788840; hg19: chr7-12395833;