14-77429038-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001193315.2(VIPAS39):ā€‹c.1324A>Gā€‹(p.Thr442Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

VIPAS39
NM_001193315.2 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29552072).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VIPAS39NM_001193315.2 linkuse as main transcriptc.1324A>G p.Thr442Ala missense_variant 18/20 ENST00000557658.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VIPAS39ENST00000557658.6 linkuse as main transcriptc.1324A>G p.Thr442Ala missense_variant 18/201 NM_001193315.2 P1Q9H9C1-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251390
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461712
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000207
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 25, 2023The c.1324A>G (p.T442A) alteration is located in exon 18 (coding exon 17) of the VIPAS39 gene. This alteration results from a A to G substitution at nucleotide position 1324, causing the threonine (T) at amino acid position 442 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.035
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.035
T;.;T;T;.;T
Eigen
Benign
-0.12
Eigen_PC
Benign
0.067
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
.;D;.;D;.;D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.30
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;.;L;L;.;.
MutationTaster
Benign
0.97
D;D;D;D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.95
N;.;N;N;N;N
REVEL
Benign
0.12
Sift
Benign
0.15
T;.;T;T;T;T
Sift4G
Benign
0.48
T;T;T;T;T;T
Polyphen
0.16
B;.;B;B;.;.
Vest4
0.46
MutPred
0.47
Gain of helix (P = 0.0128);.;Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);.;.;
MVP
0.33
MPC
0.27
ClinPred
0.24
T
GERP RS
5.5
Varity_R
0.056
gMVP
0.17

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.

Other links and lift over

dbSNP: rs769112384; hg19: chr14-77895381; API