14-77427635-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001193315.2(VIPAS39):c.1463A>G(p.Gln488Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: VIPAS39 NM_001193315.2 missense, splice_region
• Scores: Splicing: ADA: 0.7788
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIPAS39	NM_001193315.2	c.1463A>G	p.Gln488Arg	missense_variant, splice_region_variant	20/20	ENST00000557658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1463A>G	p.Gln488Arg	missense_variant, splice_region_variant	20/20	1	NM_001193315.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Feb 06, 2024

The c.1463A>G (p.Q488R) alteration is located in exon 20 (coding exon 19) of the VIPAS39 gene. This alteration results from a A to G substitution at nucleotide position 1463, causing the glutamine (Q) at amino acid position 488 to be replaced by an arginine (R). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.060	T;.;T;T;.;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.3	M;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;.;N;N;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.043	D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;.;.
Vest4		0.32
MutPred		0.67		Gain of MoRF binding (P = 0.0338);.;Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);.;.;
MVP		0.74
MPC		0.47
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.18
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Benign	0.72
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-77893978;