rs3752087

chr18-50664070-G-Achr18-50664070-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002747.4(MAPK4):c.112G>A(p.Val38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,580 control chromosomes in the GnomAD database, including 124,988 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (9140 hom., cov: 32)
  • Exomes 𝑓: 0.39 (115848 hom.)
• Consequence: MAPK4 NM_002747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.6383014E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK4	NM_002747.4	c.112G>A	p.Val38Met	missense_variant	2/6	ENST00000400384.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK4	ENST00000400384.7	c.112G>A	p.Val38Met	missense_variant	2/6	1	NM_002747.4	P1
MAPK4	ENST00000588540.1	c.112G>A	p.Val38Met	missense_variant	2/3	1
MAPK4	ENST00000592595.5	c.112G>A	p.Val38Met	missense_variant	2/4	1
MAPK4	ENST00000540640.3	c.-87-51009G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49673 AN: 151936 Hom.: 9139 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.364

GnomAD3 exomes AF: 0.366 AC: 91131 AN: 249292 Hom.: 17854 AF XY: 0.377 AC XY: 50930 AN XY: 135270

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.388

Gnomad SAS exome AF: 0.373

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.410

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.394 AC: 575847 AN: 1461528 Hom.: 115848 Cov.: 63 AF XY: 0.396 AC XY: 287819 AN XY: 727068

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.445

Gnomad4 EAS exome AF: 0.416

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.327 AC: 49671 AN: 152052 Hom.: 9140 Cov.: 32 AF XY: 0.330 AC XY: 24509 AN XY: 74318

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.367

Alfa AF: 0.393 Hom.: 29507

Bravo AF: 0.305

TwinsUK AF: 0.426 AC: 1579

ALSPAC AF: 0.408 AC: 1574

ESP6500AA AF: 0.154 AC: 650

ESP6500EA AF: 0.395 AC: 3335

ExAC AF: 0.365 AC: 44140

Asia WGS AF: 0.363 AC: 1263 AN: 3478

EpiCase AF: 0.404

EpiControl AF: 0.412

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Benign	0.95
DEOGEN2	Benign	0.023	T;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.00056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.97	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.13	T;.;.
Sift4G	Uncertain	0.057	T;T;T
Polyphen		0.94	P;.;.
Vest4		0.038
MPC		0.61
ClinPred		0.030	T
GERP RS		-4.1
Varity_R		0.11
gMVP		0.45

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: rs3752087; hg19: chr18-48190440; COSMIC: COSV68541177; COSMIC: COSV68541177;