rs1562027

chr6-161039480-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005922.4(MAP3K4):c.343+5031A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 151,900 control chromosomes in the GnomAD database, including 30,748 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 0.63 (30748 hom., cov: 30)
• Consequence: MAP3K4 NM_005922.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.384

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K4	NM_005922.4	c.343+5031A>G		intron_variant		ENST00000392142.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K4	ENST00000392142.9	c.343+5031A>G		intron_variant		1	NM_005922.4	A2

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94915 AN: 151782 Hom.: 30746 Cov.: 30

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.630

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

GnomAD4 genome AF: 0.625 AC: 94947 AN: 151900 Hom.: 30748 Cov.: 30 AF XY: 0.627 AC XY: 46549 AN XY: 74240

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.729

Gnomad4 ASJ AF: 0.775

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.696

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.697

Gnomad4 OTH AF: 0.629

Alfa AF: 0.653 Hom.: 4116

Bravo AF: 0.623

Asia WGS AF: 0.671 AC: 2334 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.1
Dann	Benign	0.75

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: rs1562027; hg19: chr6-161460512;