14-77429038-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001193315.2(VIPAS39):c.1324A>G(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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: VIPAS39 NM_001193315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

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 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
VIPAS39	NM_001193315.2	c.1324A>G	p.Thr442Ala	missense_variant	18/20	ENST00000557658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1324A>G	p.Thr442Ala	missense_variant	18/20	1	NM_001193315.2	P1

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

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

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The 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
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

Other links and lift over

dbSNP: rs769112384; hg19: chr14-77895381;