6-161034296-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005922.4(MAP3K4):​c.190C>T​(p.Pro64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,613,788 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P64H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

MAP3K4
NM_005922.4 missense

Scores

18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.003989309).
BP6
Variant 6-161034296-C-T is Benign according to our data. Variant chr6-161034296-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3898197.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 430 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP3K4NM_005922.4 linkc.190C>T p.Pro64Ser missense_variant Exon 2 of 27 ENST00000392142.9 NP_005913.3 Q9Y6R4-1Q9P1M2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP3K4ENST00000392142.9 linkc.190C>T p.Pro64Ser missense_variant Exon 2 of 27 1 NM_005922.4 ENSP00000375986.4 Q9Y6R4-1

Frequencies

GnomAD3 genomes
AF:
0.00283
AC:
431
AN:
152126
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0100
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000824
AC:
207
AN:
251082
Hom.:
2
AF XY:
0.000567
AC XY:
77
AN XY:
135708
show subpopulations
Gnomad AFR exome
AF:
0.0110
Gnomad AMR exome
AF:
0.000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000980
GnomAD4 exome
AF:
0.000328
AC:
479
AN:
1461544
Hom.:
2
Cov.:
31
AF XY:
0.000267
AC XY:
194
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.0111
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.000745
GnomAD4 genome
AF:
0.00282
AC:
430
AN:
152244
Hom.:
1
Cov.:
32
AF XY:
0.00262
AC XY:
195
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00994
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000556
Hom.:
0
Bravo
AF:
0.00343
ESP6500AA
AF:
0.00931
AC:
41
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000997
AC:
121
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MAP3K4: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
7.1
DANN
Benign
0.18
DEOGEN2
Benign
0.034
.;T;T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.79
T;T;T;T
MetaRNN
Benign
0.0040
T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.55
N;N;.;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
0.30
N;N;N;N
REVEL
Benign
0.11
Sift
Benign
0.67
T;T;T;T
Sift4G
Benign
0.18
T;T;T;T
Polyphen
0.0
B;B;.;.
Vest4
0.12
MVP
0.16
MPC
0.29
ClinPred
0.00019
T
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.024
gMVP
0.072

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.

Other links and lift over

dbSNP: rs147981479; hg19: chr6-161455328; COSMIC: COSV62333014; COSMIC: COSV62333014; API