14-77453359-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001193315.2(VIPAS39):c.136G>A(p.Val46Met) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,614,086 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 9 hom. )

Consequence

VIPAS39
NM_001193315.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.65

Variant links:

Genes affected

VIPAS39 (HGNC:20347): (VPS33B interacting protein, apical-basolateral polarity regulator, spe-39 homolog) Involved in endosome to lysosome transport and intracellular protein transport. Acts upstream of or within collagen metabolic process and peptidyl-lysine hydroxylation. Located in Golgi apparatus and endosome. Implicated in arthrogryposis, renal dysfunction, and cholestasis 2. [provided by Alliance of Genome Resources, Apr 2022]

VIPAS39 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0078122914).

BP6

Variant 14-77453359-C-T is Benign according to our data. Variant chr14-77453359-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 191049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77453359-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00113 (172/152210) while in subpopulation SAS AF= 0.00207 (10/4822). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VIPAS39	NM_001193315.2 link	c.136G>A	p.Val46Met	missense_variant	Exon 3 of 20	ENST00000557658.6	NP_001180244.1	Q9H9C1-1Q6IA61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VIPAS39	ENST00000557658.6 link	c.136G>A	p.Val46Met	missense_variant	Exon 3 of 20	1	NM_001193315.2	ENSP00000452191.1		Q9H9C1-1

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00169

AC:

426

AN:

251490

Hom.:

AF XY:

0.00173

AC XY:

235

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000914

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00141

AC:

2061

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1052

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.00228

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152210

Hom.:

Cov.:

AF XY:

0.000981

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00139

AC:

169

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VIPAS39: BS1 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Mar 08, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2016

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

VIPAS39-related disorder

Benign:1

Mar 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.045

T;.;T;T;.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D;.;D;.;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.0078

T;T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.0

M;M;M;M;M;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.73

N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0080

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.72

MVP

0.55

MPC

0.82

ClinPred

0.038

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.41

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