2-101698111-G-A

Position:

• chr2-101698111-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001395002.1(MAP4K4):​c.31G>A​(p.Val11Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000786 in 1,145,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: MAP4K4 NM_001395002.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27116418).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4K4	NM_001395002.1	c.31G>A	p.Val11Met	missense_variant	1/33	ENST00000324219.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP4K4	ENST00000324219.9	c.31G>A	p.Val11Met	missense_variant	1/33	5	NM_001395002.1	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000786 AC: 9 AN: 1145166 Hom.: 0 Cov.: 30 AF XY: 0.00000704 AC XY: 4 AN XY: 567784

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: 0.00000980

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.31G>A (p.V11M) alteration is located in exon 1 (coding exon 1) of the MAP4K4 gene. This alteration results from a G to A substitution at nucleotide position 31, causing the valine (V) at amino acid position 11 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;T;T;.;.;T;T;.;T;.
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.34	.;N;.;.;.;N;.;.;.;N;.
MutationTaster	Benign	0.87	D;D;N;N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.66	N;.;N;N;N;.;N;.;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.039	D;.;D;D;D;.;D;.;.;D;D
Sift4G	Uncertain	0.057	T;D;D;D;D;T;D;D;D;D;D
Polyphen		0.52, 0.99, 0.39	.;.;P;D;B;D;.;.;.;B;.
Vest4		0.18, 0.17, 0.19, 0.18, 0.35, 0.38, 0.34, 0.27, 0.30
MutPred		0.33		Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);
MVP		0.54
MPC		1.5
ClinPred		0.68	D
GERP RS		2.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.34
gMVP		0.68

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: rs2035271150; hg19: chr2-102314573;