rs148360332

chr14-77453359-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.65

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIPAS39	NM_001193315.2	c.136G>A	p.Val46Met	missense_variant	3/20	ENST00000557658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIPAS39	ENST00000557658.6	c.136G>A	p.Val46Met	missense_variant	3/20	1	NM_001193315.2	P1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152092 Hom.: 0 Cov.: 32

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.: 2 AF XY: 0.00173 AC XY: 235 AN XY: 135918

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.: 9 Cov.: 32 AF XY: 0.00145 AC XY: 1052 AN XY: 727244

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.: 0 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74420

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.: 4

Bravo AF: 0.00124

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2017	- -
Likely benign, criteria provided, single submitter	research	Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	Sep 28, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	VIPAS39: BS1 -

VIPAS39-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

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	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	32
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	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0078	T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
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	T
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

Other links and lift over

dbSNP: rs148360332; hg19: chr14-77919702;