rs1488

Variant names:

• chr6-161117218-G-A
• rs1488
• ENST00000490904.6:n.*3362G>A

Variant summary

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

The ENST00000490904.6(MAP3K4):​n.*3362G>A variant causes a non coding transcript exon 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 ENST00000490904.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.839
• Publications: 30 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=-0.71).
• 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 rank	MANE	Protein	UniProt
MAP3K4	NM_005922.4	c.*348G>A		3_prime_UTR_variant	Exon 27 of 27	ENST00000392142.9	NP_005913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9	c.*348G>A		3_prime_UTR_variant	Exon 27 of 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

African (AFR) AF: 0.534 AC: 1717 AN: 3218

American (AMR) AF: 0.497 AC: 1372 AN: 2762

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 2703 AN: 3574

East Asian (EAS) AF: 0.768 AC: 4890 AN: 6366

South Asian (SAS) AF: 0.790 AC: 1145 AN: 1450

European-Finnish (FIN) AF: 0.632 AC: 3582 AN: 5670

Middle Eastern (MID) AF: 0.681 AC: 338 AN: 496

European-Non Finnish (NFE) AF: 0.644 AC: 36063 AN: 56008

Other (OTH) AF: 0.647 AC: 3843 AN: 5940

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

African (AFR) AF: 0.522 AC: 21656 AN: 41452

American (AMR) AF: 0.538 AC: 8228 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2663 AN: 3470

East Asian (EAS) AF: 0.740 AC: 3824 AN: 5168

South Asian (SAS) AF: 0.799 AC: 3852 AN: 4824

European-Finnish (FIN) AF: 0.654 AC: 6912 AN: 10564

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43260 AN: 67994

Other (OTH) AF: 0.622 AC: 1315 AN: 2114

Alfa AF: 0.630 Hom.: 52600

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
PhyloP100		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1488; hg19: chr6-161538250;