7-12344236-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001135924.3(VWDE):c.4037G>A(p.Cys1346Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.4037G>A	p.Cys1346Tyr	missense_variant	21/29	ENST00000275358.8
VWDE	NM_001346972.2	c.3692G>A	p.Cys1231Tyr	missense_variant	19/27
VWDE	NM_001346973.2	c.3227G>A	p.Cys1076Tyr	missense_variant	19/27
VWDE	NR_144534.2	n.4859G>A		non_coding_transcript_exon_variant	22/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.4037G>A	p.Cys1346Tyr	missense_variant	21/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.*801G>A		3_prime_UTR_variant, NMD_transcript_variant	22/30	1
VWDE	ENST00000521169.5	c.*2415G>A		3_prime_UTR_variant, NMD_transcript_variant	18/26	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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 08, 2024

The c.4037G>A (p.C1346Y) alteration is located in exon 21 (coding exon 21) of the VWDE gene. This alteration results from a G to A substitution at nucleotide position 4037, causing the cysteine (C) at amino acid position 1346 to be replaced by a tyrosine (Y). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.1	D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.99		Loss of disorder (P = 0.086);.;
MVP		0.77
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.99

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: chr7-12383862;