16-69321169-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_013245.3(VPS4A):c.970C>T(p.Arg324Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,577,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

VPS4A
NM_013245.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Variant links:

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]

VPS4A links:

ENSG00000260914 (HGNC:):

ENSG00000260914 links:

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]

COG8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.785

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS4A	NM_013245.3 link	c.970C>T	p.Arg324Trp	missense_variant	Exon 9 of 11	ENST00000254950.13	NP_037377.1	Q9UN37A0A024R705

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS4A	ENST00000254950.13 link	c.970C>T	p.Arg324Trp	missense_variant	Exon 9 of 11	1	NM_013245.3	ENSP00000254950.11		Q9UN37
ENSG00000260914	ENST00000570054.3 link	c.1042C>T	p.Arg348Trp	missense_variant	Exon 9 of 10	5		ENSP00000461295.3		I3L4J1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000157

AC:

AN:

191324

Hom.:

AF XY:

0.00

AC XY:

AN XY:

103014

show subpopulations

Gnomad AFR exome

AF:

0.0000974

Gnomad AMR exome

AF:

0.0000696

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1425722

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

705728

show subpopulations

Gnomad4 AFR exome

AF:

0.0000617

Gnomad4 AMR exome

AF:

0.0000750

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000618

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000457

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000836

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.970C>T (p.R324W) alteration is located in exon 9 (coding exon 9) of the VPS4A gene. This alteration results from a C to T substitution at nucleotide position 970, causing the arginine (R) at amino acid position 324 to be replaced by a tryptophan (W). 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

0.16

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

.;D

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.3

.;M

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.3

.;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0030

.;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

.;D

Vest4

0.65

MVP

0.84

MPC

1.3

ClinPred

0.76

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.23

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over