7-12375099-G-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.1153C>G(p.Arg385Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000715 in 1,399,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

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=0.15685076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWDE	NM_001135924.3	c.1153C>G	p.Arg385Gly	missense_variant	8/29	ENST00000275358.8
VWDE	NM_001346972.2	c.1153C>G	p.Arg385Gly	missense_variant	8/27
VWDE	NM_001346973.2	c.688C>G	p.Arg230Gly	missense_variant	8/27
VWDE	NR_144534.2	n.1302C>G		non_coding_transcript_exon_variant	8/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8	c.1153C>G	p.Arg385Gly	missense_variant	8/29	5	NM_001135924.3	P1
VWDE	ENST00000452576.6	c.1153C>G	p.Arg385Gly	missense_variant, NMD_transcript_variant	8/30	1
VWDE	ENST00000521169.5	c.1024+2677C>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 156890 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83028

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: 0.0000164

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.00000715 AC: 10 AN: 1399020 Hom.: 0 Cov.: 32 AF XY: 0.00000580 AC XY: 4 AN XY: 690010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000560

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: 0.00000649

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.087	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Benign	0.14	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.53	P
Vest4		0.18
MutPred		0.31		Loss of stability (P = 0.0184);
MVP		0.52
ClinPred		0.21	T
GERP RS		3.8
Varity_R		0.20
gMVP		0.20

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: rs17165936; hg19: chr7-12414725;