NM_001395002.1:c.31G>A

Variant names:

• chr2-101698111-G-A
• rs2035271150
• NM_001395002.1:c.31G>A

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395002.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	NM_001395002.1	MANE Select	c.31G>A	p.Val11Met	missense	Exon 1 of 33	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.31G>A	p.Val11Met	missense	Exon 1 of 32	NP_001371426.1
	MAP4K4	NM_001384492.1		c.31G>A	p.Val11Met	missense	Exon 1 of 33	NP_001371421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.31G>A	p.Val11Met	missense	Exon 1 of 33	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.31G>A	p.Val11Met	missense	Exon 1 of 31	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.31G>A	p.Val11Met	missense	Exon 1 of 30	ENSP00000314363.6	O95819-1

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

African (AFR) AF: 0.00 AC: 0 AN: 22186

American (AMR) AF: 0.00 AC: 0 AN: 29636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14992

East Asian (EAS) AF: 0.00 AC: 0 AN: 11864

South Asian (SAS) AF: 0.00 AC: 0 AN: 71662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4236

European-Non Finnish (NFE) AF: 0.00000980 AC: 9 AN: 918052

Other (OTH) AF: 0.00 AC: 0 AN: 40214

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.34	N
PhyloP100		7.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.21
Sift	Benign	0.039	D
Sift4G	Uncertain	0.057	T
Polyphen		0.52	P
Vest4		0.18
MutPred		0.33		Gain of disorder (P = 0.0551)
MVP		0.54
MPC		1.5
ClinPred		0.68	D
GERP RS		2.2
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.34
gMVP		0.68
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs2035271150; hg19: chr2-102314573;