3-50617596-G-C

Variant names:

• chr3-50617596-G-C
• rs147044454
• NM_001243925.2:c.31G>C

Variant summary

Our verdict is Likely benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G11C) has been classified 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
• Publications: 0 publications found

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]

MAPKAPK3 Gene-Disease associations (from GenCC):

• patterned macular dystrophy 3

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243925.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK3	NM_001243925.2	MANE Select	c.31G>C	p.Gly11Arg	missense	Exon 2 of 11	NP_001230854.1	Q16644
	MAPKAPK3	NM_001243926.2		c.31G>C	p.Gly11Arg	missense	Exon 4 of 13	NP_001230855.1	Q16644
	MAPKAPK3	NM_004635.5		c.31G>C	p.Gly11Arg	missense	Exon 2 of 11	NP_004626.1	Q16644

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK3	ENST00000621469.5	TSL:1 MANE Select	c.31G>C	p.Gly11Arg	missense	Exon 2 of 11	ENSP00000478922.1	Q16644
	MAPKAPK3	ENST00000357955.6	TSL:1	c.31G>C	p.Gly11Arg	missense	Exon 2 of 11	ENSP00000350639.2	Q16644
	MAPKAPK3	ENST00000446044.5	TSL:1	c.31G>C	p.Gly11Arg	missense	Exon 4 of 13	ENSP00000396467.1	Q16644

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238322 AF XY: 0.00

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33106

American (AMR) AF: 0.0000224 AC: 1 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4512

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096076

Other (OTH) AF: 0.00 AC: 0 AN: 59596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.51
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.055
Sift	Uncertain	0.021	D
Sift4G	Benign	0.53	T
Polyphen		0.010	B
Vest4		0.14
MutPred		0.22		Loss of loop (P = 0.0128)
MVP		0.35
MPC		0.57
ClinPred		0.043	T
GERP RS		-0.37
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.24
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs147044454; hg19: chr3-50655027;