NM_002747.4:c.112G>A

Variant names:

• chr18-50664070-G-A
• rs3752087
• NM_002747.4:c.112G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.33 (9140 hom., cov: 32)
  • Exomes 𝑓: 0.39 (115848 hom.)
• Consequence: MAPK4 NM_002747.4 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.144
• Publications: 32 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002747.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK4	NM_002747.4	MANE Select	c.112G>A	p.Val38Met	missense	Exon 2 of 6	NP_002738.2
	MAPK4	NM_001292040.2		c.112G>A	p.Val38Met	missense	Exon 2 of 4	NP_001278969.1
	MAPK4	NM_001292039.2		c.-87-51009G>A		intron	N/A	NP_001278968.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK4	ENST00000400384.7	TSL:1 MANE Select	c.112G>A	p.Val38Met	missense	Exon 2 of 6	ENSP00000383234.1
	MAPK4	ENST00000588540.1	TSL:1	c.112G>A	p.Val38Met	missense	Exon 2 of 3	ENSP00000465661.1
	MAPK4	ENST00000592595.5	TSL:1	c.112G>A	p.Val38Met	missense	Exon 2 of 4	ENSP00000466233.1

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

GnomAD2 exomes AF: 0.366 AC: 91131 AN: 249292 AF XY: 0.377

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 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

African (AFR) AF: 0.149 AC: 4982 AN: 33480

American (AMR) AF: 0.232 AC: 10374 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 11642 AN: 26136

East Asian (EAS) AF: 0.416 AC: 16511 AN: 39700

South Asian (SAS) AF: 0.376 AC: 32393 AN: 86258

European-Finnish (FIN) AF: 0.434 AC: 23015 AN: 53076

Middle Eastern (MID) AF: 0.426 AC: 2458 AN: 5768

European-Non Finnish (NFE) AF: 0.406 AC: 451171 AN: 1111992

Other (OTH) AF: 0.386 AC: 23301 AN: 60394

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

African (AFR) AF: 0.154 AC: 6400 AN: 41506

American (AMR) AF: 0.308 AC: 4714 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1520 AN: 3468

East Asian (EAS) AF: 0.396 AC: 2041 AN: 5150

South Asian (SAS) AF: 0.376 AC: 1801 AN: 4792

European-Finnish (FIN) AF: 0.450 AC: 4755 AN: 10558

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.402 AC: 27357 AN: 67978

Other (OTH) AF: 0.367 AC: 773 AN: 2104

Alfa AF: 0.382 Hom.: 55516

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

ClinVar submissions as Germline

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Thalidomide response (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.00056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L
PhyloP100		0.14
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.14
Sift	Benign	0.13	T
Sift4G	Uncertain	0.057	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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