6-161108646-A-C

Variant names:

• chr6-161108646-A-C
• rs2272197
• NM_005922.4:c.4120-97A>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.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
• Publications: 2 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 (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K4	NM_005922.4	MANE Select	c.4120-97A>C		intron	N/A	NP_005913.3
	MAP3K4	NM_001301072.2		c.4108-97A>C		intron	N/A	NP_001288001.2
	MAP3K4	NM_006724.4		c.3970-97A>C		intron	N/A	NP_006715.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K4	ENST00000392142.9	TSL:1 MANE Select	c.4120-97A>C		intron	N/A	ENSP00000375986.4
	MAP3K4	ENST00000366919.6	TSL:1	c.3970-97A>C		intron	N/A	ENSP00000355886.2
	MAP3K4	ENST00000490904.6	TSL:1	n.*2307-97A>C		intron	N/A	ENSP00000446303.1

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

African (AFR) AF: 0.0757 AC: 1152 AN: 15226

American (AMR) AF: 0.0854 AC: 2549 AN: 29834

Ashkenazi Jewish (ASJ) AF: 0.0770 AC: 1292 AN: 16784

East Asian (EAS) AF: 0.240 AC: 8338 AN: 34814

South Asian (SAS) AF: 0.195 AC: 10816 AN: 55370

European-Finnish (FIN) AF: 0.155 AC: 7634 AN: 49386

Middle Eastern (MID) AF: 0.0879 AC: 321 AN: 3650

European-Non Finnish (NFE) AF: 0.168 AC: 58744 AN: 349776

Other (OTH) AF: 0.147 AC: 4496 AN: 30682

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

African (AFR) AF: 0.0767 AC: 3184 AN: 41532

American (AMR) AF: 0.115 AC: 1750 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0735 AC: 255 AN: 3470

East Asian (EAS) AF: 0.258 AC: 1335 AN: 5174

South Asian (SAS) AF: 0.205 AC: 991 AN: 4824

European-Finnish (FIN) AF: 0.157 AC: 1657 AN: 10570

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11431 AN: 68008

Other (OTH) AF: 0.108 AC: 228 AN: 2108

Alfa AF: 0.144 Hom.: 2862

Bravo AF: 0.128

Asia WGS AF: 0.228 AC: 793 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.25
DANN	Benign	0.47
PhyloP100		-1.0
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: rs2272197; hg19: chr6-161529678; COSMIC: COSV62331391; COSMIC: COSV62331391;