chr6-161048742-G-A

Variant names:

• chr6-161048742-G-A
• rs4559074
• NM_005922.4:c.470G>A

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81
• Publications: 36 publications found

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

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.

Transcripts

RefSeq

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

Ensembl

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

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

GnomAD2 exomes AF: 0.963 AC: 241423 AN: 250574 AF XY: 0.964

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

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

GnomAD4 genome AF: 0.967 AC: 147142 AN: 152238 Hom.: 71142 Cov.: 31 AF XY: 0.966 AC XY: 71865 AN XY: 74420

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

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 v4.3

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;.;.
PhyloP100		4.8
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
Mutation Taster		=99/1	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: rs4559074; hg19: chr6-161469774; COSMIC: COSV104538709;