22-38689086-T-G

Variant names:

• chr22-38689086-T-G
• rs529943159
• NM_001360236.2:c.358A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001360236.2(JOSD1):​c.358A>C​(p.Met120Leu) 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. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M120V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JOSD1 NM_001360236.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.45
• Publications: 2 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09206706).

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.358A>C	p.Met120Leu	missense	Exon 4 of 5	NP_001347165.1	Q15040
	JOSD1	NM_001360235.2		c.358A>C	p.Met120Leu	missense	Exon 4 of 5	NP_001347164.1	Q15040
	JOSD1	NM_014876.7		c.358A>C	p.Met120Leu	missense	Exon 4 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.358A>C	p.Met120Leu	missense	Exon 4 of 5	ENSP00000506752.1	Q15040
	JOSD1	ENST00000216039.9	TSL:1	c.358A>C	p.Met120Leu	missense	Exon 3 of 4	ENSP00000216039.5	Q15040
	JOSD1	ENST00000866135.1		c.358A>C	p.Met120Leu	missense	Exon 4 of 5	ENSP00000536194.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.5	N
PhyloP100		3.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.35
MutPred		0.51		Gain of sheet (P = 0.0085)
MVP		0.29
MPC		0.68
ClinPred		0.42	T
GERP RS		4.7
Varity_R		0.33
gMVP		0.35
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs529943159; hg19: chr22-39085091;