16-69322570-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP3_ModerateBP6_ModerateBS2

The NM_013245.3(VPS4A):c.1082C>A(p.Pro361His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,612,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

VPS4A
NM_013245.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.84

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:

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 -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

BP6

Variant 16-69322570-C-A is Benign according to our data. Variant chr16-69322570-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2513326.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS4A	NM_013245.3 linkuse as main transcript	c.1082C>A	p.Pro361His	missense_variant	10/11	ENST00000254950.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
VPS4A	ENST00000254950.13 linkuse as main transcript	c.1082C>A	p.Pro361His	missense_variant	10/11	1	NM_013245.3	P1
VPS4A	ENST00000566354.1 linkuse as main transcript	n.1360C>A		non_coding_transcript_exon_variant	1/2	1
COG8	ENST00000562595.5 linkuse as main transcript	c.*1013G>T		3_prime_UTR_variant	4/4	5
COG8	ENST00000564419.1 linkuse as main transcript	n.30-1524G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000967

AC:

AN:

248148

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

134652

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.0000292

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:

0.000187

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000208

AC:

304

AN:

1460634

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000184

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000744

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000297

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.29

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

.;D

Vest4

0.83

MVP

0.75

MPC

1.4

ClinPred

0.85

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.57

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