chr2-101790727-A-T

Position:

• chr2-101790727-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T;.;T;T;.;.;T;T;.;T;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.6	.;L;.;.;.;L;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D;.;D;D;D;.;D;.;.;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.061	T;.;D;D;D;.;D;.;.;D;D;D
Sift4G	Pathogenic	0.0010	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		0.68		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		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-102407189;