Variant 12-111871102-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003668.4(MAPKAPK5):c.501G>C(p.Leu167Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,012 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 (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MAPKAPK5
NM_003668.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

Variant links:

Genes affected

MAPKAPK5 (HGNC:6889): (MAPK activated protein kinase 5) The protein encoded by this gene is a tumor suppressor and member of the serine/threonine kinase family. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. The encoded protein is found in the nucleus but translocates to the cytoplasm upon phosphorylation and activation. This kinase phosphorylates heat shock protein HSP27 at its physiologically relevant sites. Two alternately spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2012]

MAPKAPK5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPKAPK5	NM_003668.4 linkuse as main transcript	c.501G>C	p.Leu167Phe	missense_variant	7/14	ENST00000550735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPKAPK5	ENST00000550735.7 linkuse as main transcript	c.501G>C	p.Leu167Phe	missense_variant	7/14	1	NM_003668.4	P4	Q8IW41-2
MAPKAPK5	ENST00000551404.7 linkuse as main transcript	c.501G>C	p.Leu167Phe	missense_variant	7/14	5		A1	Q8IW41-1
MAPKAPK5	ENST00000549875.1 linkuse as main transcript	c.54G>C	p.Leu18Phe	missense_variant	2/9	5
MAPKAPK5	ENST00000553053.5 linkuse as main transcript	c.54G>C	p.Leu18Phe	missense_variant, NMD_transcript_variant	2/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151840

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248848

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135010

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 SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461172

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74110

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:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Apr 12, 2023

The c.501G>C (p.L167F) alteration is located in exon 7 (coding exon 7) of the MAPKAPK5 gene. This alteration results from a G to C substitution at nucleotide position 501, causing the leucine (L) at amino acid position 167 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

.;T;T

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.0

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.9

D;D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.78

MutPred

0.58

Gain of methylation at K166 (P = 0.0283);Gain of methylation at K166 (P = 0.0283);.;

MVP

0.72

MPC

1.5

ClinPred

0.95

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.78

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