chr22-38699840-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38169527).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360236.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JOSD1	NM_001360236.2	MANE Select	c.148G>A	p.Ala50Thr	missense	Exon 2 of 5	NP_001347165.1	Q15040
	JOSD1	NM_001360235.2		c.148G>A	p.Ala50Thr	missense	Exon 2 of 5	NP_001347164.1	Q15040
	JOSD1	NM_014876.7		c.148G>A	p.Ala50Thr	missense	Exon 2 of 5	NP_055691.1	Q15040

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JOSD1	ENST00000683374.1	MANE Select	c.148G>A	p.Ala50Thr	missense	Exon 2 of 5	ENSP00000506752.1	Q15040
	JOSD1	ENST00000216039.9	TSL:1	c.148G>A	p.Ala50Thr	missense	Exon 1 of 4	ENSP00000216039.5	Q15040
	JOSD1	ENST00000866135.1		c.148G>A	p.Ala50Thr	missense	Exon 2 of 5	ENSP00000536194.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.44	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)
MVP		0.55
MPC		1.6
ClinPred		0.92	D
GERP RS		4.5
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.72
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

hg19: chr22-39095845;