NM_001395002.1:c.181-8022G>A

Variant names:

• chr2-101815906-G-A
• rs4851502
• NM_001395002.1:c.181-8022G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001395002.1(MAP4K4):​c.181-8022G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0802 in 152,118 control chromosomes in the GnomAD database, including 543 homozygotes. 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: 𝑓 0.080 (543 hom., cov: 32)
• Consequence: MAP4K4 NM_001395002.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.500
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	NM_001395002.1	MANE Select	c.181-8022G>A		intron	N/A	NP_001381931.1
	MAP4K4	NM_001384497.1		c.181-8022G>A		intron	N/A	NP_001371426.1
	MAP4K4	NM_001384492.1		c.181-8022G>A		intron	N/A	NP_001371421.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.181-8022G>A		intron	N/A	ENSP00000313644.6
	MAP4K4	ENST00000350878.9	TSL:1	c.181-8022G>A		intron	N/A	ENSP00000343658.5
	MAP4K4	ENST00000347699.8	TSL:1	c.181-8022G>A		intron	N/A	ENSP00000314363.6

Frequencies

GnomAD3 genomes AF: 0.0802 AC: 12188 AN: 152000 Hom.: 542 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0540

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0862

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0856

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0802 AC: 12198 AN: 152118 Hom.: 543 Cov.: 32 AF XY: 0.0809 AC XY: 6014 AN XY: 74334

African (AFR) AF: 0.0603 AC: 2500 AN: 41492

American (AMR) AF: 0.116 AC: 1770 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0540 AC: 187 AN: 3466

East Asian (EAS) AF: 0.115 AC: 592 AN: 5166

South Asian (SAS) AF: 0.104 AC: 502 AN: 4812

European-Finnish (FIN) AF: 0.0862 AC: 912 AN: 10582

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.0801 AC: 5446 AN: 68006

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0831 Hom.: 1100

Bravo AF: 0.0826

Asia WGS AF: 0.0940 AC: 326 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.93
DANN	Benign	0.69
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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: rs4851502; hg19: chr2-102432368;