18-50664470-T-C

Variant names:

• chr18-50664470-T-C
• rs909222744
• NM_002747.4:c.512T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002747.4(MAPK4):​c.512T>C​(p.Leu171Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPK4 NM_002747.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

MAPK4 (HGNC:6878): (mitogen-activated protein kinase 4) Mitogen-activated protein kinase 4 is a member of the mitogen-activated protein kinase family. Tyrosine kinase growth factor receptors activate mitogen-activated protein kinases which then translocate into the nucleus and phosphorylate nuclear targets. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK4	NM_002747.4	c.512T>C	p.Leu171Ser	missense_variant	Exon 2 of 6	ENST00000400384.7	NP_002738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK4	ENST00000400384.7	c.512T>C	p.Leu171Ser	missense_variant	Exon 2 of 6	1	NM_002747.4	ENSP00000383234.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.512T>C (p.L171S) alteration is located in exon 2 (coding exon 1) of the MAPK4 gene. This alteration results from a T to C substitution at nucleotide position 512, causing the leucine (L) at amino acid position 171 to be replaced by a serine (S). 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	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.2	D;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.90		Gain of disorder (P = 0.0276);Gain of disorder (P = 0.0276);Gain of disorder (P = 0.0276);
MVP		0.98
MPC		1.9
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.79
gMVP		0.91

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: rs909222744; hg19: chr18-48190840;