2-101790759-G-A

Variant names:

• chr2-101790759-G-A
• rs1239475028
• NM_001395002.1:c.163G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001395002.1(MAP4K4):​c.163G>A​(p.Val55Ile) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP4K4 NM_001395002.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35311475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP4K4	NM_001395002.1	c.163G>A	p.Val55Ile	missense_variant	Exon 3 of 33	ENST00000324219.9	NP_001381931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP4K4	ENST00000324219.9	c.163G>A	p.Val55Ile	missense_variant	Exon 3 of 33	5	NM_001395002.1	ENSP00000313644.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458142 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.;T;T;.;.;T;T;.;T;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.66	.;N;.;.;.;N;.;.;.;N;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.96	N;.;N;N;N;.;N;.;.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.63	T;.;T;T;T;.;T;.;.;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.85, 0.24, 0.88, 0.54	.;.;P;B;P;P;.;.;.;P;.;.
Vest4		0.39, 0.39, 0.43, 0.40, 0.43, 0.42, 0.41, 0.37, 0.42
MutPred		0.42		Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);Loss of methylation at K54 (P = 0.0569);.;
MVP		0.43
MPC		1.2
ClinPred		0.81	D
GERP RS		5.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.17
gMVP		0.74

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

Other links and lift over

dbSNP: rs1239475028; hg19: chr2-102407221;