16-69321159-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_013245.3(VPS4A):c.960C>T(p.His320=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,581,386 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (7 hom.)
• Consequence: VPS4A NM_013245.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.67

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]

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-69321159-C-T is Benign according to our data. Variant chr16-69321159-C-T is described in ClinVar as [Benign]. Clinvar id is 2646671.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.68 with no splicing effect.
• BS2: High AC in GnomAd at 438 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS4A	NM_013245.3	c.960C>T	p.His320=	synonymous_variant	9/11	ENST00000254950.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS4A	ENST00000254950.13	c.960C>T	p.His320=	synonymous_variant	9/11	1	NM_013245.3	P1
VPS4A	ENST00000564399.1	n.67C>T		non_coding_transcript_exon_variant	1/2	5
COG8	ENST00000564419.1	n.30-113G>A		intron_variant, non_coding_transcript_variant		5
VPS4A	ENST00000562754.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000659 AC: 129 AN: 195814 Hom.: 1 AF XY: 0.000455 AC XY: 48 AN XY: 105514

Gnomad AFR exome AF: 0.00972

Gnomad AMR exome AF: 0.000102

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: 0.000225

Gnomad OTH exome AF: 0.000795

GnomAD4 exome AF: 0.000416 AC: 594 AN: 1429138 Hom.: 7 Cov.: 33 AF XY: 0.000359 AC XY: 254 AN XY: 707808

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000493

Gnomad4 FIN exome AF: 0.0000592

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.000541

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74450

Gnomad4 AFR AF: 0.00994

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00297

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

VPS4A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.52
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs369039396; hg19: chr16-69355062;