16-69321143-C-T

Position:

• chr16-69321143-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_013245.3(VPS4A):​c.944C>T​(p.Thr315Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000188 in 1,436,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: VPS4A NM_013245.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23

Genes affected

VPS4A (HGNC:13488): (vacuolar protein sorting 4 homolog A) 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. The mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be really an 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 16; the gene for the other resides on chromosome 18. [provided by RefSeq, Jul 2008]

ENSG00000260914 (HGNC:):

COG8 (HGNC:18623): (component of oligomeric golgi complex 8) This gene encodes a protein that is a component of the conserved oligomeric Golgi (COG) complex, a multiprotein complex that plays a structural role in the Golgi apparatus, and is involved in intracellular membrane trafficking and glycoprotein modification. Mutations in this gene cause congenital disorder of glycosylation, type IIh, a disease that is characterized by under-glycosylated serum proteins, and whose symptoms include severe psychomotor retardation, failure to thrive, seizures, and dairy and wheat product intolerance. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS4A	NM_013245.3	c.944C>T	p.Thr315Met	missense_variant	9/11	ENST00000254950.13	NP_037377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS4A	ENST00000254950.13	c.944C>T	p.Thr315Met	missense_variant	9/11	1	NM_013245.3	ENSP00000254950.11
ENSG00000260914	ENST00000570054.3	c.1016C>T	p.Thr339Met	missense_variant	9/10	5		ENSP00000461295.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000485 AC: 1 AN: 206088 Hom.: 0 AF XY: 0.00000897 AC XY: 1 AN XY: 111440

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: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000188 AC: 27 AN: 1436734 Hom.: 0 Cov.: 33 AF XY: 0.00000983 AC XY: 7 AN XY: 712328

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.0000218

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Mar 01, 2023

The missense c.944C>T (p.Thr315Met)variant in VPS4A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Thr315Met variant has allele freuency 0.0005% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Thr315Met in VPS4A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 315 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.2	.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	.;D
Vest4		0.46
MutPred		0.35		.;Loss of phosphorylation at T315 (P = 0.0966);
MVP		0.78
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.51

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: rs1443596563; hg19: chr16-69355046;