7-12356162-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001135924.3(VWDE):c.3694T>G(p.Tyr1232Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 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)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.3694T>G	p.Tyr1232Asp	missense_variant	18/29	ENST00000275358.8
VWDE	NM_001346972.2	c.3349T>G	p.Tyr1117Asp	missense_variant	16/27
VWDE	NM_001346973.2	c.2884T>G	p.Tyr962Asp	missense_variant	16/27
VWDE	NR_144534.2	n.3843T>G		non_coding_transcript_exon_variant	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.3694T>G	p.Tyr1232Asp	missense_variant	18/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.3694T>G	p.Tyr1232Asp	missense_variant, NMD_transcript_variant	18/30	1
VWDE	ENST00000644150.1	c.169T>G	p.Tyr57Asp	missense_variant	1/3
VWDE	ENST00000521169.5	c.*2072T>G		3_prime_UTR_variant, NMD_transcript_variant	15/26	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Jul 19, 2022

The c.3694T>G (p.Y1232D) alteration is located in exon 18 (coding exon 18) of the VWDE gene. This alteration results from a T to G substitution at nucleotide position 3694, causing the tyrosine (Y) at amino acid position 1232 to be replaced by an aspartic acid (D). 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	0.15
BayesDel_addAF	Benign	0.00034	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Benign	0.91
DEOGEN2	Benign	0.032	T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.18	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.91	N;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.029	D;T;.
Polyphen		0.0010	B;.;.
Vest4		0.27
MutPred		0.85		Gain of disorder (P = 0.0083);.;.;
MVP		0.50
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.25
gMVP		0.78

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: rs1266411996; hg19: chr7-12395788;