19-50506412-C-T

Position:

• chr19-50506412-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000598418.6(JOSD2):​c.433G>A​(p.Ala145Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 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)
• Consequence: JOSD2 ENST00000598418.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

JOSD2 (HGNC:28853): (Josephin domain containing 2) This gene encodes a protein containing a Josephin domain. Josephin domain-containing proteins are deubiquitinating enzymes which catalyze the hydrolysis of the bond between the C-terminal glycine of the ubiquitin peptide and protein substrates. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21745169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JOSD2	NM_001270639.2	c.433G>A	p.Ala145Thr	missense_variant	4/5	ENST00000598418.6	NP_001257568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JOSD2	ENST00000598418.6	c.433G>A	p.Ala145Thr	missense_variant	4/5	1	NM_001270639.2	ENSP00000468956	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.433G>A (p.A145T) alteration is located in exon 4 (coding exon 3) of the JOSD2 gene. This alteration results from a G to A substitution at nucleotide position 433, causing the alanine (A) at amino acid position 145 to be replaced by a threonine (T). 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	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.026	T;T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.76	.;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.83	P;P;.;.
Vest4		0.22
MutPred		0.38		Gain of phosphorylation at A145 (P = 0.0295);Gain of phosphorylation at A145 (P = 0.0295);.;Gain of phosphorylation at A145 (P = 0.0295);
MVP		0.33
MPC		0.28
ClinPred		0.34	T
GERP RS		2.2
Varity_R		0.076
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51009669;