16-69321219-C-G

Variant names:

• chr16-69321219-C-G
• NM_013245.3:c.1020C>G

Variant summary

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

The NM_013245.3(VPS4A):​c.1020C>G​(p.Asp340Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS4A NM_013245.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.195

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS4A	NM_013245.3	c.1020C>G	p.Asp340Glu	missense_variant	Exon 9 of 11	ENST00000254950.13	NP_037377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS4A	ENST00000254950.13	c.1020C>G	p.Asp340Glu	missense_variant	Exon 9 of 11	1	NM_013245.3	ENSP00000254950.11
ENSG00000260914	ENST00000570054.3	c.1092C>G	p.Asp364Glu	missense_variant	Exon 9 of 10	5		ENSP00000461295.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1020C>G (p.D340E) alteration is located in exon 9 (coding exon 9) of the VPS4A gene. This alteration results from a C to G substitution at nucleotide position 1020, causing the aspartic acid (D) at amino acid position 340 to be replaced by a glutamic acid (E). 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	0.75
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.24	.;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	.;D
REVEL	Uncertain	0.57
Sift	Benign	0.13	.;T
Sift4G	Benign	0.36	T;T
Polyphen		0.036	.;B
Vest4		0.83
MutPred		0.63		.;Loss of catalytic residue at D340 (P = 0.0679);
MVP		0.39
MPC		0.82
ClinPred		0.71	D
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.28
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-69355122;