22-41601108-C-A

Variant names:

• chr22-41601108-C-A
• rs144622202
• NM_015704.3:c.496G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015704.3(DESI1):​c.496G>T​(p.Gly166Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. G166S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DESI1 NM_015704.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• Publications: 4 publications found

Genes affected

DESI1 (HGNC:24577): (desumoylating isopeptidase 1) Enables importin-alpha family protein binding activity. Involved in protein export from nucleus and regulation of proteasomal ubiquitin-dependent protein catabolic process. Located in cytosol. Part of protein-containing complex. [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=0.32474422).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015704.3. 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
	DESI1	NM_015704.3	MANE Select	c.496G>T	p.Gly166Cys	missense	Exon 6 of 6	NP_056519.1	Q6ICB0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DESI1	ENST00000263256.7	TSL:1 MANE Select	c.496G>T	p.Gly166Cys	missense	Exon 6 of 6	ENSP00000263256.6	Q6ICB0
	DESI1	ENST00000938248.1		c.496G>T	p.Gly166Cys	missense	Exon 6 of 6	ENSP00000608307.1
	DESI1	ENST00000881058.1		c.451G>T	p.Gly151Cys	missense	Exon 6 of 6	ENSP00000551117.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.14		Loss of phosphorylation at S168 (P = 0.0727)
MVP		0.51
MPC		1.5
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.30
gMVP		0.81
Mutation Taster		=71/29	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

dbSNP: rs144622202; hg19: chr22-41997112;