rs4559074

Variant names:

Variant summary

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

The NM_005922.4(MAP3K4):c.470G>A(p.Arg157His) variant causes a missense change. The variant allele was found at a frequency of 0.958 in 1,614,030 control chromosomes in the GnomAD database, including 740,608 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.97 ( 71142 hom., cov: 31)

Exomes 𝑓: 0.96 ( 669466 hom. )

Consequence

MAP3K4
NM_005922.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.81

Publications

36 publications found

Variant links:

Genes affected

MAP3K4 (HGNC:6856): (mitogen-activated protein kinase kinase kinase 4) The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 and SERK1, MAPKKs that activate CSBP2 and JNK, respectively but cannot phosphorylate PRKMK1, an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the CSBP2 MAPK pathway, and a minor mediator of the JNK pathway. Several alternatively spliced transcripts encoding distinct isoforms have been described. [provided by RefSeq, May 2014]

MAP3K4 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=8.1831234E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K4	NM_005922.4	MANE Select	c.470G>A	p.Arg157His	missense	Exon 3 of 27	NP_005913.3	Q9Y6R4-1
MAP3K4	NM_001301072.2		c.470G>A	p.Arg157His	missense	Exon 3 of 27	NP_001288001.2	F5H538
MAP3K4	NM_006724.4		c.470G>A	p.Arg157His	missense	Exon 3 of 26	NP_006715.3	Q9Y6R4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K4	ENST00000392142.9	TSL:1 MANE Select	c.470G>A	p.Arg157His	missense	Exon 3 of 27	ENSP00000375986.4	Q9Y6R4-1
MAP3K4	ENST00000366919.6	TSL:1	c.470G>A	p.Arg157His	missense	Exon 3 of 26	ENSP00000355886.2	Q9Y6R4-2
MAP3K4	ENST00000490904.6	TSL:1	n.470G>A		non_coding_transcript_exon	Exon 3 of 28	ENSP00000446303.1	F5H1X6

Frequencies

GnomAD3 genomes

AF:

0.967

AC:

147029

AN:

152120

Hom.:

71088

Cov.:

show subpopulations

Gnomad AFR

AF:

0.991

Gnomad AMI

AF:

0.998

Gnomad AMR

AF:

0.975

Gnomad ASJ

AF:

0.995

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.990

Gnomad FIN

AF:

0.914

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

0.951

Gnomad OTH

AF:

0.971

GnomAD2 exomes

AF:

0.963

AC:

241423

AN:

250574

AF XY:

0.964

show subpopulations

Gnomad AFR exome

AF:

0.994

Gnomad AMR exome

AF:

0.966

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

0.998

Gnomad FIN exome

AF:

0.916

Gnomad NFE exome

AF:

0.952

Gnomad OTH exome

AF:

0.965

GnomAD4 exome

AF:

0.957

AC:

1398794

AN:

1461792

Hom.:

669466

Cov.:

AF XY:

0.958

AC XY:

696630

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.993

AC:

33254

AN:

33476

American (AMR)

AF:

0.969

AC:

43329

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.993

AC:

25963

AN:

26136

East Asian (EAS)

AF:

0.995

AC:

39515

AN:

39700

South Asian (SAS)

AF:

0.988

AC:

85189

AN:

86258

European-Finnish (FIN)

AF:

0.914

AC:

48767

AN:

53372

Middle Eastern (MID)

AF:

0.990

AC:

5711

AN:

5768

European-Non Finnish (NFE)

AF:

0.952

AC:

1058726

AN:

1111968

Other (OTH)

AF:

0.966

AC:

58340

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

3421

6843

10264

13686

17107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21622

43244

64866

86488

108110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.967

AC:

147142

AN:

152238

Hom.:

71142

Cov.:

AF XY:

0.966

AC XY:

71865

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.991

AC:

41192

AN:

41546

American (AMR)

AF:

0.975

AC:

14923

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.995

AC:

3453

AN:

3472

East Asian (EAS)

AF:

0.997

AC:

5153

AN:

5166

South Asian (SAS)

AF:

0.989

AC:

4774

AN:

4826

European-Finnish (FIN)

AF:

0.914

AC:

9680

AN:

10586

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

0.951

AC:

64710

AN:

68016

Other (OTH)

AF:

0.971

AC:

2055

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

254

507

761

1014

1268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.961

Hom.:

216286

Bravo

AF:

0.970

TwinsUK

AF:

0.950

AC:

3521

ALSPAC

AF:

0.953

AC:

3672

ESP6500AA

AF:

0.992

AC:

4372

ESP6500EA

AF:

0.956

AC:

8221

ExAC

AF:

0.964

AC:

117020

Asia WGS

AF:

0.992

AC:

3452

AN:

3478

EpiCase

AF:

0.960

EpiControl

AF:

0.961

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.037

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.54

MetaRNN

Benign

8.2e-7

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.5

PhyloP100

4.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

2.0

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.094

MPC

0.36

ClinPred

0.0062

GERP RS

6.0

Varity_R

0.085

gMVP

0.20

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over