7-12351649-A-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.3810T>G(p.Ser1270Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.400

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=0.08471471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.3810T>G	p.Ser1270Arg	missense_variant	19/29	ENST00000275358.8
VWDE	NM_001346972.2	c.3465T>G	p.Ser1155Arg	missense_variant	17/27
VWDE	NM_001346973.2	c.3000T>G	p.Ser1000Arg	missense_variant	17/27
VWDE	NR_144534.2	n.4632T>G		non_coding_transcript_exon_variant	20/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.3810T>G	p.Ser1270Arg	missense_variant	19/29	5	NM_001135924.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000642 AC: 1 AN: 155836 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398164 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000193 Hom.: 0

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

Jun 22, 2023

The c.3810T>G (p.S1270R) alteration is located in exon 19 (coding exon 19) of the VWDE gene. This alteration results from a T to G substitution at nucleotide position 3810, causing the serine (S) at amino acid position 1270 to be replaced by an arginine (R). 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	-0.072	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	2.8
Dann	Benign	0.90
DEOGEN2	Benign	0.023	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.63	T;.;.
Sift4G	Benign	0.30	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.14
MutPred		0.45		Gain of methylation at K1269 (P = 0.0475);.;.;
MVP		0.15
ClinPred		0.025	T
GERP RS		-0.82
Varity_R		0.095
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs561187344; hg19: chr7-12391275;