Genetic Variant DUSP5:p.Leu47Val (chr10-110498260-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004419.4(DUSP5):c.139C>G(p.Leu47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,500,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L47P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DUSP5
NM_004419.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.950

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.139C>G	p.Leu47Val	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.139C>G	p.Leu47Val	missense	Exon 1 of 4	ENSP00000358596.3	Q16690
DUSP5	ENST00000925260.1		c.139C>G	p.Leu47Val	missense	Exon 1 of 4	ENSP00000595319.1
DUSP5	ENST00000895745.1		c.139C>G	p.Leu47Val	missense	Exon 1 of 2	ENSP00000565804.1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149674

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183662

AF XY:

0.0000192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1350384

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

672824

show subpopulations

African (AFR)

AF:

0.0000360

AC:

AN:

27750

American (AMR)

AF:

0.00

AC:

AN:

36944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22612

East Asian (EAS)

AF:

0.00

AC:

AN:

29808

South Asian (SAS)

AF:

0.0000504

AC:

AN:

79388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1055522

Other (OTH)

AF:

0.0000184

AC:

AN:

54322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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

AF:

0.0000134

AC:

AN:

149674

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41146

American (AMR)

AF:

0.00

AC:

AN:

15064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67072

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000170

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.3

PhyloP100

0.95

PrimateAI

Pathogenic

0.97

PROVEAN

Benign

-0.99

REVEL

Benign

0.14

Sift

Benign

0.14

Sift4G

Benign

0.26

Polyphen

0.86

Vest4

0.31

MutPred

0.44

Gain of catalytic residue at L47 (P = 0.0567)

MVP

0.76

MPC

1.1

ClinPred

0.56

GERP RS

5.0

PromoterAI

0.19

Neutral

(source)

Varity_R

0.39

gMVP

0.51

Mutation Taster

=26/74

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over