7-12337200-T-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.4439A>T(p.Tyr1480Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 33)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

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=0.21488863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.4439A>T	p.Tyr1480Phe	missense_variant	25/29	ENST00000275358.8
VWDE	NM_001346972.2	c.4094A>T	p.Tyr1365Phe	missense_variant	23/27
VWDE	NM_001346973.2	c.3629A>T	p.Tyr1210Phe	missense_variant	23/27
VWDE	NR_144534.2	n.5261A>T		non_coding_transcript_exon_variant	26/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.4439A>T	p.Tyr1480Phe	missense_variant	25/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.*1203A>T		3_prime_UTR_variant, NMD_transcript_variant	26/30	1
VWDE	ENST00000521169.5	c.*2817A>T		3_prime_UTR_variant, NMD_transcript_variant	22/26	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Oct 05, 2021

The c.4439A>T (p.Y1480F) alteration is located in exon 25 (coding exon 25) of the VWDE gene. This alteration results from a A to T substitution at nucleotide position 4439, causing the tyrosine (Y) at amino acid position 1480 to be replaced by a phenylalanine (F). 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	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.022	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.91	L;.
MutationTaster	Benign	0.88	N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.16
Sift	Benign	0.059	T;.
Sift4G	Benign	0.13	T;D
Polyphen		1.0	D;.
Vest4		0.20
MutPred		0.44		Gain of disorder (P = 0.0747);.;
MVP		0.030
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.46
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-12376826;