10-110498261-T-C

Variant names:

• chr10-110498261-T-C
• rs867741891
• NM_004419.4:c.140T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004419.4(DUSP5):​c.140T>C​(p.Leu47Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000111 in 1,347,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DUSP5 NM_004419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

Genes affected

DUSP5 (HGNC:3071): (dual specificity phosphatase 5) 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 are 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 inactivates ERK1, is expressed in a variety of tissues with the highest levels in pancreas and brain, and is localized in the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUSP5	NM_004419.4	c.140T>C	p.Leu47Pro	missense_variant	Exon 1 of 4	ENST00000369583.4	NP_004410.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUSP5	ENST00000369583.4	c.140T>C	p.Leu47Pro	missense_variant	Exon 1 of 4	1	NM_004419.4	ENSP00000358596.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000111 AC: 15 AN: 1347608 Hom.: 0 Cov.: 31 AF XY: 0.00000596 AC XY: 4 AN XY: 671424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000142

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140T>C (p.L47P) alteration is located in exon 1 (coding exon 1) of the DUSP5 gene. This alteration results from a T to C substitution at nucleotide position 140, causing the leucine (L) at amino acid position 47 to be replaced by a proline (P). 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	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.98	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.81		Loss of stability (P = 0.0158);
MVP		0.85
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.90

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: rs867741891; hg19: chr10-112258019;