14-77428474-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001193315.2(VIPAS39):c.1357A>T(p.Thr453Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VIPAS39 NM_001193315.2 missense, splice_region
• Scores: Splicing: ADA: 0.8762
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIPAS39	NM_001193315.2	c.1357A>T	p.Thr453Ser	missense_variant, splice_region_variant	19/20	ENST00000557658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1357A>T	p.Thr453Ser	missense_variant, splice_region_variant	19/20	1	NM_001193315.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461540 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with VIPAS39-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 453 of the VIPAS39 protein (p.Thr453Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.057	T;.;T;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	M;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;.;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.059	T;.;T;T;T;T
Sift4G	Benign	0.077	T;T;T;T;T;T
Polyphen		0.96	D;.;D;D;.;.
Vest4		0.65
MutPred		0.83		Gain of disorder (P = 0.0817);.;Gain of disorder (P = 0.0817);Gain of disorder (P = 0.0817);.;.;
MVP		0.51
MPC		0.77
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-77894817;