rs4559074

Positions:

• chr6-161048742-G-A

Variant summary

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

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.97 (71142 hom., cov: 31)
  • Exomes 𝑓: 0.96 (669466 hom.)
• Consequence: MAP3K4 NM_005922.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81

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]

ACMG classification

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/exons	MANE	Protein	UniProt
MAP3K4	NM_005922.4	c.470G>A	p.Arg157His	missense_variant	3/27	ENST00000392142.9	NP_005913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9	c.470G>A	p.Arg157His	missense_variant	3/27	1	NM_005922.4	ENSP00000375986	A2

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147029 AN: 152120 Hom.: 71088 Cov.: 31

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

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.: 61 AF XY: 0.958 AC XY: 696630 AN XY: 727200

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.: 31 AF XY: 0.966 AC XY: 71865 AN XY: 74420

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	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.037	.;T;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.54	T;T;T;T
MetaRNN	Benign	8.2e-7	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.5	N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs4559074; hg19: chr6-161469774;