7-12356188-T-G

Variant summary

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

The NM_001135924.3(VWDE):c.3668A>C(p.Gln1223Pro) 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. 15/20 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: 0.718

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=0.1379931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.3668A>C	p.Gln1223Pro	missense_variant	18/29	ENST00000275358.8
VWDE	NM_001346972.2	c.3323A>C	p.Gln1108Pro	missense_variant	16/27
VWDE	NM_001346973.2	c.2858A>C	p.Gln953Pro	missense_variant	16/27
VWDE	NR_144534.2	n.3817A>C		non_coding_transcript_exon_variant	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.3668A>C	p.Gln1223Pro	missense_variant	18/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.3668A>C	p.Gln1223Pro	missense_variant, NMD_transcript_variant	18/30	1
VWDE	ENST00000644150.1	c.143A>C	p.Gln48Pro	missense_variant	1/3
VWDE	ENST00000521169.5	c.*2046A>C		3_prime_UTR_variant, NMD_transcript_variant	15/26	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

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

Dec 27, 2023

The c.3668A>C (p.Q1223P) alteration is located in exon 18 (coding exon 18) of the VWDE gene. This alteration results from a A to C substitution at nucleotide position 3668, causing the glutamine (Q) at amino acid position 1223 to be replaced by a proline (P). 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	0.083
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	17
Dann	Benign	0.57
DEOGEN2	Benign	0.019	T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.090	N
LIST_S2	Uncertain	0.90	D;D;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Benign	0.16
Sift	Benign	0.26	T;.;.
Sift4G	Benign	0.24	T;T;.
Polyphen		0.73	P;.;.
Vest4		0.30
MutPred		0.48		Gain of disorder (P = 0.05);.;.;
MVP		0.22
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.70

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: chr7-12395814;