chrX-153650174-C-T

Position:

• chrX-153650174-C-T

Variant summary

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

The NM_001318503.2(DUSP9):​c.1024C>T​(p.Arg342Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R342H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: DUSP9 NM_001318503.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.364

Genes affected

DUSP9 (HGNC:3076): (dual specificity phosphatase 9) The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which is associated with cellular proliferation and differentiation. Different members of the family of dual specificity phosphatases show distinct substrate specificities for various MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. This gene product shows selectivity for members of the ERK family of MAP kinases and is localized to the cytoplasm and nucleus. Aberrant expression of this gene is associated with type 2 diabetes and cancer progression in several cell types. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUSP9	NM_001318503.2	c.1024C>T	p.Arg342Cys	missense_variant	4/4	ENST00000342782.4
DUSP9	NM_001395.4	c.1024C>T	p.Arg342Cys	missense_variant	4/4
DUSP9	XM_011531123.2	c.1117C>T	p.Arg373Cys	missense_variant	4/4
DUSP9	XM_047441899.1	c.1090C>T	p.Arg364Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUSP9	ENST00000342782.4	c.1024C>T	p.Arg342Cys	missense_variant	4/4	1	NM_001318503.2	P1
DUSP9	ENST00000370167.8	c.1024C>T	p.Arg342Cys	missense_variant	4/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

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

Feb 15, 2023

The c.1024C>T (p.R342C) alteration is located in exon 4 (coding exon 3) of the DUSP9 gene. This alteration results from a C to T substitution at nucleotide position 1024, causing the arginine (R) at amino acid position 342 to be replaced by a cysteine (C). 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	0.23
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;D
FATHMM_MKL	Benign	0.74	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.37
MutPred		0.54		Loss of disorder (P = 0.0334);Loss of disorder (P = 0.0334);
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs930024777; hg19: chrX-152915629;