7-12336991-T-C

Position:

• chr7-12336991-T-C

Variant summary

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

The NM_001135924.3(VWDE):​c.4555A>G​(p.Thr1519Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 3.56

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]

VWDE (HGNC:):

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=0.12056732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWDE	NM_001135924.3	c.4555A>G	p.Thr1519Ala	missense_variant	26/29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2	c.4210A>G	p.Thr1404Ala	missense_variant	24/27		NP_001333901.1
VWDE	NM_001346973.2	c.3745A>G	p.Thr1249Ala	missense_variant	24/27		NP_001333902.1
VWDE	NR_144534.2	n.5377A>G		non_coding_transcript_exon_variant	27/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8	c.4555A>G	p.Thr1519Ala	missense_variant	26/29	5	NM_001135924.3	ENSP00000275358.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 14, 2024

The c.4555A>G (p.T1519A) alteration is located in exon 26 (coding exon 26) of the VWDE gene. This alteration results from a A to G substitution at nucleotide position 4555, causing the threonine (T) at amino acid position 1519 to be replaced by an alanine (A). 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	0.095
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.043
Sift	Uncertain	0.029	D
Sift4G	Benign	0.11	T
Polyphen		0.17	B
Vest4		0.35
MutPred		0.20		Loss of phosphorylation at T1519 (P = 0.0323);
MVP		0.072
ClinPred		0.73	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1192818426; hg19: chr7-12376617;