4-86159439-T-A

Position:

chr4-86159439-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_138982.4(MAPK10):c.95A>T(p.Tyr32Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000745 in 1,611,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MAPK10
NM_138982.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

Variant links:

Genes affected

MAPK10 (HGNC:6872): (mitogen-activated protein kinase 10) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as integration points for multiple biochemical signals, and thus are involved in a wide variety of cellular processes, such as proliferation, differentiation, transcription regulation and development. This kinase is specifically expressed in a subset of neurons in the nervous system, and is activated by threonine and tyrosine phosphorylation. Targeted deletion of this gene in mice suggests that it may have a role in stress-induced neuronal apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

MAPK10 links:

MAPK10-AS1 (HGNC:):

MAPK10-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAPK10. . Gene score misZ 3.0399 (greater than the threshold 3.09). Trascript score misZ 3.6358 (greater than threshold 3.09). GenCC has associacion of gene with Lennox-Gastaut syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.24426189).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK10	NM_138982.4 linkuse as main transcript	c.95A>T	p.Tyr32Phe	missense_variant	4/14	ENST00000641462.2	NP_620448.1	P53779-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK10	ENST00000641462.2 linkuse as main transcript	c.95A>T	p.Tyr32Phe	missense_variant	4/14		NM_138982.4	ENSP00000493435.1		P53779-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249760

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135020

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459458

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

725992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000899

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.00

Bravo

AF:

0.0000151

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 29, 2021

The c.95A>T (p.Y32F) alteration is located in exon 4 (coding exon 2) of the MAPK10 gene. This alteration results from a A to T substitution at nucleotide position 95, causing the tyrosine (Y) at amino acid position 32 to be replaced by a phenylalanine (F). 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

0.071

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.23

.;.;T;T;T;T;T;T;T;.;.;T;.;.;.;T;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;T;T;.;.;.;.;.;T;T;.;.;.;.;T;.;.;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;D;.;D;D;.;.;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.24

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.34

.;.;N;N;N;N;N;N;N;.;.;N;.;N;.;N;N;.;N;N;N;.;.;N;N;N;.;.;N;.;.;N;N;.;N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.34

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;N;N;.;.;.;D;.;.;.;.;.

REVEL

Benign

0.19

Sift

Benign

0.31

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;T;T;.;.;.;T;.;.;.;.;.

Sift4G

Benign

0.088

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.71, 0.81

.;.;P;P;P;P;P;P;P;.;.;P;.;P;.;P;P;.;P;P;P;.;.;P;P;P;.;.;P;.;.;P;P;.;P;P;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.53

MutPred

0.34

Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);.;Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);.;Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);Gain of methylation at K35 (P = 0.092);

MVP

0.60

ClinPred

0.28

GERP RS

4.3

Varity_R

0.11

gMVP

0.49

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