rs2272197

Variant names:

• chr6-161108646-A-C
• rs2272197
• NM_005922.4:c.4120-97A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-161108646-A-C
• chr6-161108646-A-G

Variant summary

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

The NM_005922.4(MAP3K4):​c.4120-97A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 737,686 control chromosomes in the GnomAD database, including 10,004 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 0.14 (1619 hom., cov: 32)
  • Exomes 𝑓: 0.16 (8385 hom.)
• Consequence: MAP3K4 NM_005922.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K4	NM_005922.4	c.4120-97A>C		intron_variant	Intron 21 of 26	ENST00000392142.9	NP_005913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K4	ENST00000392142.9	c.4120-97A>C		intron_variant	Intron 21 of 26	1	NM_005922.4	ENSP00000375986.4

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20940 AN: 152046 Hom.: 1619 Cov.: 32

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0735

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.163 AC: 95342 AN: 585522 Hom.: 8385 AF XY: 0.164 AC XY: 51278 AN XY: 312168

Gnomad4 AFR exome AF: 0.0757

Gnomad4 AMR exome AF: 0.0854

Gnomad4 ASJ exome AF: 0.0770

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.138 AC: 20955 AN: 152164 Hom.: 1619 Cov.: 32 AF XY: 0.138 AC XY: 10257 AN XY: 74390

Gnomad4 AFR AF: 0.0767

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0735

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.108

Alfa AF: 0.146 Hom.: 2302

Bravo AF: 0.128

Asia WGS AF: 0.228 AC: 793 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	0.25
DANN	Benign	0.47

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: rs2272197; hg19: chr6-161529678; COSMIC: COSV62331391; COSMIC: COSV62331391;