Variant 2-101698111-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.16

Variant links:

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]

MAP4K4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MAP4K4	NM_001395002.1 link	c.31G>A	p.Val11Met	missense_variant	Exon 1 of 33	ENST00000324219.9	NP_001381931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP4K4	ENST00000324219.9 link	c.31G>A	p.Val11Met	missense_variant	Exon 1 of 33	5	NM_001395002.1	ENSP00000313644.6		G5E948

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000786

AC:

AN:

1145166

Hom.:

Cov.:

AF XY:

0.00000704

AC XY:

AN XY:

567784

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

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

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.34

.;N;.;.;.;N;.;.;.;N;.

PrimateAI

Pathogenic

0.83

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over