1-221702507-T-A

Position:

• chr1-221702507-T-A

Variant summary

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

The NM_007207.6(DUSP10):​c.1354A>T​(p.Met452Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DUSP10 NM_007207.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

DUSP10 (HGNC:3065): (dual specificity phosphatase 10) Dual specificity protein phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the MAP kinase superfamily, which is associated with cellular proliferation and differentiation. Different members of this family of dual specificity phosphatases show distinct substrate specificities for MAP kinases, different tissue distribution and subcellular localization, and different modes of expression induction by extracellular stimuli. This gene product binds to and inactivates p38 and SAPK/JNK. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

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
DUSP10	NM_007207.6	c.1354A>T	p.Met452Leu	missense_variant	4/4	ENST00000366899.4
DUSP10	XM_047442948.1	c.571A>T	p.Met191Leu	missense_variant	3/3
DUSP10	NR_111939.2	n.601A>T		non_coding_transcript_exon_variant	3/3
DUSP10	NR_111940.2	n.652A>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUSP10	ENST00000366899.4	c.1354A>T	p.Met452Leu	missense_variant	4/4	1	NM_007207.6	P1
DUSP10	ENST00000468085.5	c.*315A>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	1
DUSP10	ENST00000477026.5	c.*315A>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	2
DUSP10	ENST00000494642.1	c.*315A>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.1354A>T (p.M452L) alteration is located in exon 4 (coding exon 3) of the DUSP10 gene. This alteration results from a A to T substitution at nucleotide position 1354, causing the methionine (M) at amino acid position 452 to be replaced by a leucine (L). 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	0.89
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.41
Sift	Benign	0.15	T
Sift4G	Benign	0.077	T
Polyphen		0.99	D
Vest4		0.59
MutPred		0.72		Gain of catalytic residue at M452 (P = 0.248);
MVP		0.70
MPC		1.0
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-221875849; COSMIC: COSV60458693;