18-63393489-A-G

Position:

• chr18-63393489-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004869.4(VPS4B):​c.1153T>C​(p.Ser385Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,612,996 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: VPS4B NM_004869.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22378603).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS4B	NM_004869.4	c.1153T>C	p.Ser385Pro	missense_variant	10/11	ENST00000238497.10	NP_004860.2
VPS4B	XM_047437949.1	c.799T>C	p.Ser267Pro	missense_variant	7/8		XP_047293905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS4B	ENST00000238497.10	c.1153T>C	p.Ser385Pro	missense_variant	10/11	1	NM_004869.4	ENSP00000238497	P1
VPS4B	ENST00000588323.1	n.169T>C		non_coding_transcript_exon_variant	2/3	3
VPS4B	ENST00000588059.5	c.*667T>C		3_prime_UTR_variant, NMD_transcript_variant	8/8	5		ENSP00000465944

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000496 AC: 124 AN: 250170 Hom.: 1 AF XY: 0.000540 AC XY: 73 AN XY: 135216

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000757

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000385 AC: 563 AN: 1460660 Hom.: 2 Cov.: 30 AF XY: 0.000424 AC XY: 308 AN XY: 726634

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000292

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000345

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74496

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000491 Hom.: 1

Bravo AF: 0.000348

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000877

EpiControl AF: 0.00101

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

Sep 01, 2021

The c.1153T>C (p.S385P) alteration is located in exon 10 (coding exon 10) of the VPS4B gene. This alteration results from a T to C substitution at nucleotide position 1153, causing the serine (S) at amino acid position 385 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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.023	D
Sift4G	Benign	0.061	T
Polyphen		0.18	B
Vest4		0.56
MVP		0.96
MPC		0.99
ClinPred		0.17	T
GERP RS		5.9
Varity_R		0.91
gMVP		0.78

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: rs140107443; hg19: chr18-61060722;