3-184853940-A-G

Variant summary

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

The NM_001009921.3(VPS8):c.905A>G(p.His302Arg) 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. 13/21 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: VPS8 NM_001009921.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

Genes affected

VPS8 (HGNC:29122): (VPS8 subunit of CORVET complex) Predicted to enable metal ion binding activity. Involved in endosomal vesicle fusion. Located in early endosome. [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=0.16242993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS8	NM_001009921.3	c.905A>G	p.His302Arg	missense_variant	12/48	ENST00000625842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS8	ENST00000625842.3	c.905A>G	p.His302Arg	missense_variant	12/48	5	NM_001009921.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

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 09, 2022

The c.905A>G (p.H302R) alteration is located in exon 12 (coding exon 11) of the VPS8 gene. This alteration results from a A to G substitution at nucleotide position 905, causing the histidine (H) at amino acid position 302 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	0.098
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Benign	0.49
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0027
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.95	T;T;D;.
Sift4G	Benign	0.94	T;T;T;T
Polyphen		0.099, 0.089	.;B;B;.
Vest4		0.17
MutPred		0.37		.;Gain of solvent accessibility (P = 0.039);Gain of solvent accessibility (P = 0.039);.;
MVP		0.43
ClinPred		0.77	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.47

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: rs1724770507; hg19: chr3-184571728;