7-12356249-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001135924.3(VWDE):c.3607C>A(p.Leu1203Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,399,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000043 (0 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3952145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.3607C>A	p.Leu1203Met	missense_variant	18/29	ENST00000275358.8
VWDE	NM_001346972.2	c.3262C>A	p.Leu1088Met	missense_variant	16/27
VWDE	NM_001346973.2	c.2797C>A	p.Leu933Met	missense_variant	16/27
VWDE	NR_144534.2	n.3756C>A		non_coding_transcript_exon_variant	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.3607C>A	p.Leu1203Met	missense_variant	18/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.3607C>A	p.Leu1203Met	missense_variant, NMD_transcript_variant	18/30	1
VWDE	ENST00000644150.1	c.82C>A	p.Leu28Met	missense_variant	1/3
VWDE	ENST00000521169.5	c.*1985C>A		3_prime_UTR_variant, NMD_transcript_variant	15/26	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1399392 Hom.: 0 Cov.: 35 AF XY: 0.00000290 AC XY: 2 AN XY: 690200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.00000463

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

Jun 24, 2022

The c.3607C>A (p.L1203M) alteration is located in exon 18 (coding exon 18) of the VWDE gene. This alteration results from a C to A substitution at nucleotide position 3607, causing the leucine (L) at amino acid position 1203 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.032	T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Uncertain	-0.0058	T
MutationAssessor	Benign	0.71	N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.89	N;.;.
REVEL	Benign	0.28
Sift	Benign	0.13	T;.;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.26
MutPred		0.43		Loss of catalytic residue at L1203 (P = 0.0408);.;.;
MVP		0.14
ClinPred		0.43	T
GERP RS		-0.0051
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.047
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-12395875;