rs2314378

Variant names:

• chr6-161059100-A-G
• rs2314378
• NM_005922.4:c.1707+9121A>G

Variant summary

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

The NM_005922.4(MAP3K4):​c.1707+9121A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 151,972 control chromosomes in the GnomAD database, including 4,731 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 0.21 (4731 hom., cov: 32)
• Consequence: MAP3K4 NM_005922.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.347
• Publications: 3 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K4	NM_005922.4	c.1707+9121A>G		intron_variant	Intron 3 of 26	ENST00000392142.9	NP_005913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9	c.1707+9121A>G		intron_variant	Intron 3 of 26	1	NM_005922.4	ENSP00000375986.4

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32248 AN: 151858 Hom.: 4721 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.215

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

GnomAD4 genome AF: 0.213 AC: 32309 AN: 151972 Hom.: 4731 Cov.: 32 AF XY: 0.211 AC XY: 15684 AN XY: 74286

African (AFR) AF: 0.420 AC: 17380 AN: 41394

American (AMR) AF: 0.134 AC: 2048 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 415 AN: 3472

East Asian (EAS) AF: 0.275 AC: 1423 AN: 5178

South Asian (SAS) AF: 0.200 AC: 962 AN: 4806

European-Finnish (FIN) AF: 0.107 AC: 1124 AN: 10550

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8264 AN: 68008

Other (OTH) AF: 0.217 AC: 455 AN: 2098

Alfa AF: 0.179 Hom.: 459

Bravo AF: 0.221

Asia WGS AF: 0.247 AC: 859 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.82
PhyloP100		-0.35
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: rs2314378; hg19: chr6-161480132;