NM_013245.3:c.349G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_013245.3(VPS4A):c.349G>A(p.Val117Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,612,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

VPS4A
NM_013245.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.43

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07910162).

BP6

Variant 16-69318828-G-A is Benign according to our data. Variant chr16-69318828-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2594373.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS4A	NM_013245.3 link	c.349G>A	p.Val117Ile	missense_variant	Exon 5 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.349G>A	p.Val117Ile	missense_variant	Exon 5 of 11	1	NM_013245.3	ENSP00000254950.11		Q9UN37
ENSG00000260914	ENST00000570054.3 link	c.421G>A	p.Val141Ile	missense_variant	Exon 5 of 10	5		ENSP00000461295.3		I3L4J1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000684

AC:

AN:

248364

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000560

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461050

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726792

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151948

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000497

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jul 25, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.073

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.089

.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.079

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

-0.84

.;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.71

.;N

REVEL

Uncertain

0.32

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

.;B

Vest4

0.13

MutPred

0.55

.;Loss of ubiquitination at K121 (P = 0.0675);

MVP

0.25

MPC

0.70

ClinPred

0.041

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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