NM_005922.4:c.2823+557T>C

Variant names:

• chr6-161088511-T-C
• rs1404269
• NM_005922.4:c.2823+557T>C

Variant summary

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

The NM_005922.4(MAP3K4):​c.2823+557T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 152,052 control chromosomes in the GnomAD database, including 47,591 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 0.79 (47591 hom., cov: 31)
• Consequence: MAP3K4 NM_005922.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K4	NM_005922.4	c.2823+557T>C		intron_variant	Intron 10 of 26	ENST00000392142.9	NP_005913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9	c.2823+557T>C		intron_variant	Intron 10 of 26	1	NM_005922.4	ENSP00000375986.4

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119778 AN: 151934 Hom.: 47585 Cov.: 31

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.881

Gnomad EAS AF: 0.970

Gnomad SAS AF: 0.873

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.847

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.802

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

GnomAD4 genome AF: 0.788 AC: 119832 AN: 152052 Hom.: 47591 Cov.: 31 AF XY: 0.794 AC XY: 58991 AN XY: 74316

African (AFR) AF: 0.686 AC: 28402 AN: 41418

American (AMR) AF: 0.848 AC: 12974 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 3058 AN: 3470

East Asian (EAS) AF: 0.970 AC: 5022 AN: 5178

South Asian (SAS) AF: 0.873 AC: 4201 AN: 4812

European-Finnish (FIN) AF: 0.808 AC: 8543 AN: 10572

Middle Eastern (MID) AF: 0.853 AC: 249 AN: 292

European-Non Finnish (NFE) AF: 0.808 AC: 54923 AN: 67996

Other (OTH) AF: 0.801 AC: 1691 AN: 2110

Alfa AF: 0.806 Hom.: 27476

Bravo AF: 0.789

Asia WGS AF: 0.889 AC: 3094 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.57
DANN	Benign	0.36
PhyloP100		-0.23
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: rs1404269; hg19: chr6-161509543;