11-1556865-G-A

Position:

chr11-1556865-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004420.3(DUSP8):c.1531C>T(p.Pro511Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,124,416 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

DUSP8
NM_004420.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07813674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUSP8	NM_004420.3 linkuse as main transcript	c.1531C>T	p.Pro511Ser	missense_variant	7/7	ENST00000397374.8	NP_004411.2	Q13202
DUSP8	XM_011519932.3 linkuse as main transcript	c.1531C>T	p.Pro511Ser	missense_variant	7/7		XP_011518234.1	Q13202
DUSP8	XM_011519933.3 linkuse as main transcript	c.1531C>T	p.Pro511Ser	missense_variant	7/7		XP_011518235.1	Q13202
DUSP8	XM_047426513.1 linkuse as main transcript	c.1489C>T	p.Pro497Ser	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.1531C>T	p.Pro511Ser	missense_variant	7/7	1	NM_004420.3	ENSP00000380530.3		Q13202
DUSP8	ENST00000331588.4 linkuse as main transcript	c.1531C>T	p.Pro511Ser	missense_variant	6/6	1		ENSP00000329539.4		Q13202

Frequencies

GnomAD3 genomes

AF:

0.000601

AC:

AN:

148164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

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:

0.00

Gnomad OTH

AF:

0.000491

GnomAD4 exome

AF:

0.0000348

AC:

AN:

976144

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

458930

show subpopulations

Gnomad4 AFR exome

AF:

0.00151

Gnomad4 AMR exome

AF:

0.000586

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:

0.00

Gnomad4 OTH exome

AF:

0.0000555

GnomAD4 genome

AF:

0.000600

AC:

AN:

148272

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

72264

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000485

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000642

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

Oct 27, 2021

The c.1531C>T (p.P511S) alteration is located in exon 7 (coding exon 6) of the DUSP8 gene. This alteration results from a C to T substitution at nucleotide position 1531, causing the proline (P) at amino acid position 511 to be replaced by a serine (S). 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

0.074

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.040

T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.89

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.078

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

L;L

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.91

N;N

REVEL

Benign

0.087

Sift

Benign

0.19

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.012

B;B

Vest4

0.038

MutPred

0.23

Loss of catalytic residue at P511 (P = 0.0116);Loss of catalytic residue at P511 (P = 0.0116);

MVP

0.32

MPC

1.3

ClinPred

0.12

GERP RS

3.8

Varity_R

0.092

gMVP

0.37

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