18-50664255-C-A

Position:

• chr18-50664255-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002747.4(MAPK4):​c.297C>A​(p.Ser99Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,176 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: 𝑓 0.000026 (0 hom., cov: 32)
• Consequence: MAPK4 NM_002747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.768

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30317354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK4	NM_002747.4	c.297C>A	p.Ser99Arg	missense_variant	2/6	ENST00000400384.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK4	ENST00000400384.7	c.297C>A	p.Ser99Arg	missense_variant	2/6	1	NM_002747.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.73	N;.;.
MutationTaster	Benign	0.54	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.030	N;.;.
REVEL	Benign	0.066
Sift	Benign	0.076	T;.;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.019	B;.;.
Vest4		0.28
MutPred		0.52		Gain of ubiquitination at K97 (P = 0.0544);Gain of ubiquitination at K97 (P = 0.0544);Gain of ubiquitination at K97 (P = 0.0544);
MVP		0.80
MPC		0.86
ClinPred		0.45	T
GERP RS		3.2
Varity_R		0.083
gMVP		0.67

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: rs200651462; hg19: chr18-48190625;