6-161113583-C-T

Variant names:

• chr6-161113583-C-T
• rs9365252
• NM_005922.4:c.4626+809C>T

Variant summary

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

The NM_005922.4(MAP3K4):​c.4626+809C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 151,930 control chromosomes in the GnomAD database, including 43,554 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 0.75 (43554 hom., cov: 30)
• Consequence: MAP3K4 NM_005922.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.263
• Publications: 4 publications found

Genes affected

MAP3K4 (HGNC:6856): (mitogen-activated protein kinase kinase kinase 4) The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 and SERK1, MAPKKs that activate CSBP2 and JNK, respectively but cannot phosphorylate PRKMK1, an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the CSBP2 MAPK pathway, and a minor mediator of the JNK pathway. Several alternatively spliced transcripts encoding distinct isoforms have been described. [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005922.4. 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
	MAP3K4	NM_005922.4	MANE Select	c.4626+809C>T		intron	N/A	NP_005913.3
	MAP3K4	NM_001301072.2		c.4614+809C>T		intron	N/A	NP_001288001.2
	MAP3K4	NM_006724.4		c.4476+809C>T		intron	N/A	NP_006715.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K4	ENST00000392142.9	TSL:1 MANE Select	c.4626+809C>T		intron	N/A	ENSP00000375986.4
	MAP3K4	ENST00000366919.6	TSL:1	c.4476+809C>T		intron	N/A	ENSP00000355886.2
	MAP3K4	ENST00000490904.6	TSL:1	n.*2813+809C>T		intron	N/A	ENSP00000446303.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113541 AN: 151812 Hom.: 43546 Cov.: 30

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.970

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.758

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

GnomAD4 genome AF: 0.748 AC: 113587 AN: 151930 Hom.: 43554 Cov.: 30 AF XY: 0.754 AC XY: 56000 AN XY: 74246

African (AFR) AF: 0.557 AC: 23024 AN: 41338

American (AMR) AF: 0.828 AC: 12641 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2977 AN: 3470

East Asian (EAS) AF: 0.970 AC: 5015 AN: 5170

South Asian (SAS) AF: 0.862 AC: 4146 AN: 4808

European-Finnish (FIN) AF: 0.808 AC: 8547 AN: 10572

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54657 AN: 67978

Other (OTH) AF: 0.758 AC: 1601 AN: 2112

Alfa AF: 0.781 Hom.: 24456

Bravo AF: 0.742

Asia WGS AF: 0.874 AC: 3039 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.52
PhyloP100		-0.26
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: rs9365252; hg19: chr6-161534615;