2-101698483-G-C

Position:

• chr2-101698483-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001395002.1(MAP4K4):​c.68G>C​(p.Gly23Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 9.21

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
• PP2: Missense variant where missense usually causes diseases, MAP4K4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K4	NM_001395002.1	c.68G>C	p.Gly23Ala	missense_variant	2/33	ENST00000324219.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP4K4	ENST00000324219.9	c.68G>C	p.Gly23Ala	missense_variant	2/33	5	NM_001395002.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jan 24, 2022

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;.;T;T;.;.;T;T;.;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.022	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.7	D;.;D;D;D;.;D;.;.;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.021	D;.;D;D;D;.;D;.;.;D;D
Sift4G	Uncertain	0.045	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.99, 1.0, 0.99	.;.;D;D;D;D;.;.;.;D;.
Vest4		0.56, 0.54, 0.50, 0.55, 0.48, 0.49, 0.59, 0.47, 0.57, 0.48
MutPred		0.39		Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);Loss of catalytic residue at A22 (P = 0.0754);
MVP		0.79
MPC		1.6
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.77
gMVP		0.81

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: chr2-102314945;