22-38699840-C-T

Variant names:

• chr22-38699840-C-T
• NM_001360236.2:c.148G>A

Variant summary

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

The NM_001360236.2(JOSD1):​c.148G>A​(p.Ala50Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JOSD1 NM_001360236.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

JOSD1 (HGNC:28953): (Josephin domain containing 1) Predicted to enable thiol-dependent deubiquitinase. Predicted to be involved in protein deubiquitination. Located in membrane. [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=0.38169527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JOSD1	NM_001360236.2	c.148G>A	p.Ala50Thr	missense_variant	Exon 2 of 5	ENST00000683374.1	NP_001347165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JOSD1	ENST00000683374.1	c.148G>A	p.Ala50Thr	missense_variant	Exon 2 of 5		NM_001360236.2	ENSP00000506752.1

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

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148G>A (p.A50T) alteration is located in exon 1 (coding exon 1) of the JOSD1 gene. This alteration results from a G to A substitution at nucleotide position 148, causing the alanine (A) at amino acid position 50 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	Pathogenic	0.70
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.44	T;T;T;T;T
Sift4G	Benign	0.43	T;.;.;.;.
Polyphen		0.96	D;.;.;.;.
Vest4		0.66
MutPred		0.26		Loss of catalytic residue at A50 (P = 0.0511);Loss of catalytic residue at A50 (P = 0.0511);Loss of catalytic residue at A50 (P = 0.0511);Loss of catalytic residue at A50 (P = 0.0511);Loss of catalytic residue at A50 (P = 0.0511);
MVP		0.55
MPC		1.6
ClinPred		0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.72

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: chr22-39095845;