2-101790727-A-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001395002.1(MAP4K4):c.131A>T(p.His44Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
MAP4K4
NM_001395002.1 missense
NM_001395002.1 missense
Scores
10
2
7
Clinical Significance
Conservation
PhyloP100: 6.89
Genes affected
MAP4K4 (HGNC:6866): (mitogen-activated protein kinase kinase kinase kinase 4) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.912
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAP4K4 | NM_001395002.1 | c.131A>T | p.His44Leu | missense_variant | 3/33 | ENST00000324219.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAP4K4 | ENST00000324219.9 | c.131A>T | p.His44Leu | missense_variant | 3/33 | 5 | NM_001395002.1 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T;.;T;T;.;.;T;T;.;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.;.;.;L;.;.;.;L;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D;D;.;D;.;.;D;D;D
REVEL
Pathogenic
Sift
Benign
T;.;D;D;D;.;D;.;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.98, 0.83, 0.98, 0.97
.;.;D;P;D;D;.;.;.;D;.;.
Vest4
0.72, 0.74, 0.76, 0.79, 0.75, 0.74, 0.73, 0.74, 0.82, 0.78
MutPred
Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);.;
MVP
MPC
1.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.