3-50617596-G-C

Position:

• chr3-50617596-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001243925.2(MAPKAPK3):​c.31G>C​(p.Gly11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAPKAPK3 NM_001243925.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.508

Genes affected

MAPKAPK3 (HGNC:6888): (MAPK activated protein kinase 3) This gene encodes a member of the Ser/Thr protein kinase family. This kinase functions as a mitogen-activated protein kinase (MAP kinase)- activated protein kinase. MAP kinases are also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This kinase was shown to be activated by growth inducers and stress stimulation of cells. In vitro studies demonstrated that ERK, p38 MAP kinase and Jun N-terminal kinase were all able to phosphorylate and activate this kinase, which suggested the role of this kinase as an integrative element of signaling in both mitogen and stress responses. This kinase was reported to interact with, phosphorylate and repress the activity of E47, which is a basic helix-loop-helix transcription factor known to be involved in the regulation of tissue-specific gene expression and cell differentiation. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051689833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPKAPK3	NM_001243925.2	c.31G>C	p.Gly11Arg	missense_variant	2/11	ENST00000621469.5	NP_001230854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPKAPK3	ENST00000621469.5	c.31G>C	p.Gly11Arg	missense_variant	2/11	1	NM_001243925.2	ENSP00000478922	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000420 AC: 1 AN: 238322 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 0.00000139 AC: 2 AN: 1441318 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 717572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with MAPKAPK3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the MAPKAPK3 protein (p.Gly11Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.69
DEOGEN2	Benign	0.090	T;T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.76	.;T;T;.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.052	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.56	N;N;.;N;N
REVEL	Benign	0.055
Sift	Uncertain	0.021	D;D;.;D;D
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.010	B;.;B;B;.
Vest4		0.14
MutPred		0.22		Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP		0.35
MPC		0.57
ClinPred		0.043	T
GERP RS		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.24

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

Other links and lift over

dbSNP: rs147044454; hg19: chr3-50655027;