rs775240653

Variant names:

• chr18-63410334-C-A
• rs775240653
• NM_004869.4:c.252G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-63410334-C-A
• chr18-63410334-C-G
• chr18-63410334-C-T

Variant summary

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

The NM_004869.4(VPS4B):​c.252G>T​(p.Gln84His) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS4B NM_004869.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.696

Genes affected

VPS4B (HGNC:10895): (vacuolar protein sorting 4 homolog B) The protein encoded by this gene is a member of the AAA protein family (ATPases associated with diverse cellular activities), and is the homolog of the yeast Vps4 protein. In humans, two paralogs of the yeast protein have been identified. The former share a high degree of aa sequence similarity with each other, and also with yeast Vps4 and mouse Skd1 proteins. Mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be a yeast Vps4 ortholog. Functional studies indicate that both human paralogs associate with the endosomal compartments, and are involved in intracellular protein trafficking, similar to Vps4 protein in yeast. The gene encoding this paralog has been mapped to chromosome 18; the gene for the other resides on chromosome 16. [provided by RefSeq, Jul 2008]

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=0.10434386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS4B	NM_004869.4	c.252G>T	p.Gln84His	missense_variant	Exon 3 of 11	ENST00000238497.10	NP_004860.2
VPS4B	XM_047437949.1	c.-35G>T		5_prime_UTR_variant	Exon 1 of 8		XP_047293905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS4B	ENST00000238497.10	c.252G>T	p.Gln84His	missense_variant	Exon 3 of 11	1	NM_004869.4	ENSP00000238497.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.091	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.017
Sift	Benign	0.062	T;.
Sift4G	Benign	0.087	T;T
Polyphen		0.089	B;.
Vest4		0.19
MutPred		0.22		Loss of methylation at K79 (P = 0.0818);Loss of methylation at K79 (P = 0.0818);
MVP		0.18
MPC		0.93
ClinPred		0.15	T
GERP RS		3.2
Varity_R		0.039
gMVP		0.25

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: rs775240653; hg19: chr18-61077567;