rs1488

Positions:

• chr6-161117218-G-A

Variant summary

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

The NM_005922.4(MAP3K4):​c.*348G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 237,566 control chromosomes in the GnomAD database, including 46,916 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 0.61 (28597 hom., cov: 33)
  • Exomes 𝑓: 0.65 (18319 hom.)
• Consequence: MAP3K4 NM_005922.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.839

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=-0.71).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K4	NM_005922.4	c.*348G>A		3_prime_UTR_variant	27/27	ENST00000392142.9	NP_005913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9	c.*348G>A		3_prime_UTR_variant	27/27	1	NM_005922.4	ENSP00000375986.4

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92537 AN: 151964 Hom.: 28599 Cov.: 33

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.741

Gnomad SAS AF: 0.799

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.621

GnomAD4 exome AF: 0.651 AC: 55653 AN: 85484 Hom.: 18319 Cov.: 0 AF XY: 0.653 AC XY: 28051 AN XY: 42954

Gnomad4 AFR exome AF: 0.534

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.756

Gnomad4 EAS exome AF: 0.768

Gnomad4 SAS exome AF: 0.790

Gnomad4 FIN exome AF: 0.632

Gnomad4 NFE exome AF: 0.644

Gnomad4 OTH exome AF: 0.647

GnomAD4 genome AF: 0.609 AC: 92569 AN: 152082 Hom.: 28597 Cov.: 33 AF XY: 0.615 AC XY: 45723 AN XY: 74330

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.538

Gnomad4 ASJ AF: 0.767

Gnomad4 EAS AF: 0.740

Gnomad4 SAS AF: 0.799

Gnomad4 FIN AF: 0.654

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.622

Alfa AF: 0.635 Hom.: 42419

Bravo AF: 0.592

Asia WGS AF: 0.759 AC: 2641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.9
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1488; hg19: chr6-161538250;