18-50726154-A-G

Position:

• chr18-50726154-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002747.4(MAPK4):​c.1046A>G​(p.Asn349Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MAPK4 NM_002747.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.994

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1204499).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK4	NM_002747.4	c.1046A>G	p.Asn349Ser	missense_variant	5/6	ENST00000400384.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK4	ENST00000400384.7	c.1046A>G	p.Asn349Ser	missense_variant	5/6	1	NM_002747.4	P1
MAPK4	ENST00000592595.5	c.692-3004A>G		intron_variant		1
MAPK4	ENST00000540640.3	c.413A>G	p.Asn138Ser	missense_variant	4/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.1046A>G (p.N349S) alteration is located in exon 5 (coding exon 4) of the MAPK4 gene. This alteration results from a A to G substitution at nucleotide position 1046, causing the asparagine (N) at amino acid position 349 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	Benign	0.061
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.50	D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.063
Sift	Benign	0.12	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.075	B;.
Vest4		0.098
MutPred		0.33		Gain of disorder (P = 0.0498);.;
MVP		0.39
MPC		0.48
ClinPred		0.11	T
GERP RS		-3.9
Varity_R		0.057
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-48252524;