dbSNP rs3752087: MAPK4:p.Val38Met (chr18-50664070-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 0.144

Publications

32 publications found

Variant links:

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]

MAPK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK4	NM_002747.4 link	c.112G>A	p.Val38Met	missense_variant	Exon 2 of 6	ENST00000400384.7	NP_002738.2	P31152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK4	ENST00000400384.7 link	c.112G>A	p.Val38Met	missense_variant	Exon 2 of 6	1	NM_002747.4	ENSP00000383234.1		P31152

Frequencies

GnomAD3 genomes

AF:

0.327

AC:

49673

AN:

151936

Hom.:

9139

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.396

AC XY:

287819

AN XY:

727068

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

23169

46339

69508

92678

115847

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.327

AC:

49671

AN:

152052

Hom.:

9140

Cov.:

AF XY:

0.330

AC XY:

24509

AN XY:

74318

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1617

3233

4850

6466

8083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thalidomide response

Other:1

Rare Diseases Genetics and Genomics, Islamia College Peshawar

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

this variant was associated with excellent response to thalidomide (achieving transfusion independence) excellent responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.023

T;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.00056

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.89

L;.;.

PhyloP100

0.14

PrimateAI

Benign

0.25

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

GERP RS

-4.1

Varity_R

0.11

gMVP

0.45

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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rs3752087

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over