Variant rs4559074 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K4	NM_005922.4 link	c.470G>A	p.Arg157His	missense_variant	Exon 3 of 27	ENST00000392142.9	NP_005913.3	Q9Y6R4-1Q9P1M2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9 link	c.470G>A	p.Arg157His	missense_variant	Exon 3 of 27	1	NM_005922.4	ENSP00000375986.4		Q9Y6R4-1

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

GnomAD3 exomes

AF:

0.963

AC:

241423

AN:

250574

Hom.:

116361

AF XY:

0.964

AC XY:

130700

AN XY:

135516

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 SAS exome

AF:

0.988

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

Gnomad4 AFR exome

AF:

0.993

Gnomad4 AMR exome

AF:

0.969

Gnomad4 ASJ exome

AF:

0.993

Gnomad4 EAS exome

AF:

0.995

Gnomad4 SAS exome

AF:

0.988

Gnomad4 FIN exome

AF:

0.914

Gnomad4 NFE exome

AF:

0.952

Gnomad4 OTH exome

AF:

0.966

GnomAD4 genome

AF:

0.967

AC:

147142

AN:

152238

Hom.:

71142

Cov.:

AF XY:

0.966

AC XY:

71865

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.991

Gnomad4 AMR

AF:

0.975

Gnomad4 ASJ

AF:

0.995

Gnomad4 EAS

AF:

0.997

Gnomad4 SAS

AF:

0.989

Gnomad4 FIN

AF:

0.914

Gnomad4 NFE

AF:

0.951

Gnomad4 OTH

AF:

0.971

Alfa

AF:

0.960

Hom.:

143667

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.037

.;T;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.54

T;T;T;T

MetaRNN

Benign

8.2e-7

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.5

N;N;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

2.0

N;N;N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.094

MPC

0.36

ClinPred

0.0062

GERP RS

6.0

Varity_R

0.085

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over