3-50617620-C-A

Position:

• chr3-50617620-C-A

Variant summary

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

The NM_001243925.2(MAPKAPK3):​c.55C>A​(p.Pro19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.283

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=0.06771076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPKAPK3	NM_001243925.2	c.55C>A	p.Pro19Thr	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.55C>A	p.Pro19Thr	missense_variant	2/11	1	NM_001243925.2	ENSP00000478922	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000414 AC: 1 AN: 241396 Hom.: 0 AF XY: 0.00000758 AC XY: 1 AN XY: 131906

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000939

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453482 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 723136

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Dec 11, 2023

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 19 of the MAPKAPK3 protein (p.Pro19Thr). This variant is present in population databases (rs779772290, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with MAPKAPK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 2129143). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Benign	0.097	T;T;T;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.59	.;T;T;.;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.068	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.51	N;N;.;N;N
REVEL	Benign	0.067
Sift	Benign	0.69	T;T;.;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.010	B;.;B;B;.
Vest4		0.15
MutPred		0.23		Gain of phosphorylation at P19 (P = 0.0078);Gain of phosphorylation at P19 (P = 0.0078);Gain of phosphorylation at P19 (P = 0.0078);Gain of phosphorylation at P19 (P = 0.0078);Gain of phosphorylation at P19 (P = 0.0078);
MVP		0.77
MPC		0.52
ClinPred		0.036	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.30

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: rs779772290; hg19: chr3-50655051;