chr11-1556981-A-C

Position:

chr11-1556981-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004420.3(DUSP8):c.1415T>G(p.Leu472Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 1,038,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

DUSP8
NM_004420.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16

Variant links:

Genes affected

DUSP8 (HGNC:3074): (dual specificity phosphatase 8) 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 inactivates SAPK/JNK and p38, is expressed predominantly in the adult brain, heart, and skeletal muscle, is localized in the cytoplasm, and is induced by nerve growth factor and insulin. An intronless pseudogene for DUSP8 is present on chromosome 10q11.2. [provided by RefSeq, Jul 2008]

DUSP8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3163398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP8	NM_004420.3 linkuse as main transcript	c.1415T>G	p.Leu472Arg	missense_variant	7/7	ENST00000397374.8	NP_004411.2	Q13202
DUSP8	XM_011519932.3 linkuse as main transcript	c.1415T>G	p.Leu472Arg	missense_variant	7/7		XP_011518234.1	Q13202
DUSP8	XM_011519933.3 linkuse as main transcript	c.1415T>G	p.Leu472Arg	missense_variant	7/7		XP_011518235.1	Q13202
DUSP8	XM_047426513.1 linkuse as main transcript	c.1373T>G	p.Leu458Arg	missense_variant	7/7		XP_047282469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUSP8	ENST00000397374.8 linkuse as main transcript	c.1415T>G	p.Leu472Arg	missense_variant	7/7	1	NM_004420.3	ENSP00000380530.3		Q13202
DUSP8	ENST00000331588.4 linkuse as main transcript	c.1415T>G	p.Leu472Arg	missense_variant	6/6	1		ENSP00000329539.4		Q13202

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

146500

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000303

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000448

AC:

AN:

892482

Hom.:

Cov.:

AF XY:

0.0000571

AC XY:

AN XY:

420030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000749

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:

0.0000424

Gnomad4 OTH exome

AF:

0.0000984

GnomAD4 genome

AF:

0.0000137

AC:

AN:

146500

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000303

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

The c.1415T>G (p.L472R) alteration is located in exon 7 (coding exon 6) of the DUSP8 gene. This alteration results from a T to G substitution at nucleotide position 1415, causing the leucine (L) at amino acid position 472 to be replaced by an arginine (R). 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

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.045

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.52

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.12

Sift

Benign

0.35

T;T

Sift4G

Benign

0.088

T;T

Polyphen

0.97

D;D

Vest4

0.20

MutPred

0.46

Gain of methylation at L472 (P = 0.0143);Gain of methylation at L472 (P = 0.0143);

MVP

0.49

MPC

2.3

ClinPred

0.57

GERP RS

3.8

Varity_R

0.26

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over