Genetic Variant NM_004419.4:c.140T>C (chr10-110498261-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L47F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DUSP5
NM_004419.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

Publications

0 publications found

Variant links:

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]

DUSP5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004419.4. 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
	DUSP5	NM_004419.4	MANE Select	c.140T>C	p.Leu47Pro	missense	Exon 1 of 4	NP_004410.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DUSP5	ENST00000369583.4	TSL:1 MANE Select	c.140T>C	p.Leu47Pro	missense	Exon 1 of 4	ENSP00000358596.3	Q16690
DUSP5	ENST00000925260.1		c.140T>C	p.Leu47Pro	missense	Exon 1 of 4	ENSP00000595319.1
DUSP5	ENST00000895745.1		c.140T>C	p.Leu47Pro	missense	Exon 1 of 2	ENSP00000565804.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1347608

Hom.:

Cov.:

AF XY:

0.00000596

AC XY:

AN XY:

671424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27714

American (AMR)

AF:

0.00

AC:

AN:

36726

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22504

East Asian (EAS)

AF:

0.00

AC:

AN:

29698

South Asian (SAS)

AF:

0.00

AC:

AN:

79014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5344

European-Non Finnish (NFE)

AF:

0.0000142

AC:

AN:

1053930

Other (OTH)

AF:

0.00

AC:

AN:

54152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.6

PhyloP100

3.6

PrimateAI

Pathogenic

0.98

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.58

Sift

Uncertain

0.023

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.85

MutPred

0.81

Loss of stability (P = 0.0158)

MVP

0.85

MPC

2.5

ClinPred

0.99

GERP RS

5.0

PromoterAI

-0.0050

Neutral

(source)

Varity_R

0.81

gMVP

0.90

Mutation Taster

=1/99

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over