18-50664086-G-A

Position:

• chr18-50664086-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002747.4(MAPK4):​c.128G>A​(p.Cys43Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,658 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: 0.0000041 (0 hom.)
• Consequence: MAPK4 NM_002747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.95

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1934875).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK4	NM_002747.4	c.128G>A	p.Cys43Tyr	missense_variant	2/6	ENST00000400384.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK4	ENST00000400384.7	c.128G>A	p.Cys43Tyr	missense_variant	2/6	1	NM_002747.4	P1
MAPK4	ENST00000588540.1	c.128G>A	p.Cys43Tyr	missense_variant	2/3	1
MAPK4	ENST00000592595.5	c.128G>A	p.Cys43Tyr	missense_variant	2/4	1
MAPK4	ENST00000540640.3	c.-87-50993G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249366 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135322

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461658 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727144

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.77
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.74	N;.;.
MutationTaster	Benign	0.80	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.30	N;.;.
REVEL	Benign	0.057
Sift	Benign	0.037	D;.;.
Sift4G	Uncertain	0.037	D;D;D
Polyphen		0.092	B;.;.
Vest4		0.30
MutPred		0.38		Gain of MoRF binding (P = 0.0739);Gain of MoRF binding (P = 0.0739);Gain of MoRF binding (P = 0.0739);
MVP		0.75
MPC		1.5
ClinPred		0.27	T
GERP RS		4.1
Varity_R		0.23
gMVP		0.78

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: rs775288765; hg19: chr18-48190456;