rs2314379

Variant names:

• chr6-161045148-G-A
• rs2314379
• NM_005922.4:c.344-3468G>A

Variant summary

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

The NM_005922.4(MAP3K4):​c.344-3468G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 151,736 control chromosomes in the GnomAD database, including 11,056 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 0.35 (11056 hom., cov: 31)
• Consequence: MAP3K4 NM_005922.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K4	NM_005922.4	c.344-3468G>A		intron_variant	Intron 2 of 26	ENST00000392142.9	NP_005913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9	c.344-3468G>A		intron_variant	Intron 2 of 26	1	NM_005922.4	ENSP00000375986.4

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53680 AN: 151618 Hom.: 11052 Cov.: 31

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.390

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

GnomAD4 genome AF: 0.354 AC: 53696 AN: 151736 Hom.: 11056 Cov.: 31 AF XY: 0.359 AC XY: 26603 AN XY: 74144

African (AFR) AF: 0.142 AC: 5869 AN: 41358

American (AMR) AF: 0.519 AC: 7921 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1972 AN: 3468

East Asian (EAS) AF: 0.181 AC: 931 AN: 5150

South Asian (SAS) AF: 0.461 AC: 2215 AN: 4808

European-Finnish (FIN) AF: 0.414 AC: 4338 AN: 10486

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29062 AN: 67884

Other (OTH) AF: 0.388 AC: 820 AN: 2112

Alfa AF: 0.427 Hom.: 19071

Bravo AF: 0.355

Asia WGS AF: 0.344 AC: 1200 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		0.079
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: rs2314379; hg19: chr6-161466180;