chr6-161034296-C-T

Variant names:

• chr6-161034296-C-T
• rs147981479
• NM_005922.4:c.190C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005922.4(MAP3K4):​c.190C>T​(p.Pro64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,613,788 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P64H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: MAP3K4 NM_005922.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.89
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003989309).
• BP6: Variant 6-161034296-C-T is Benign according to our data. Variant chr6-161034296-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3898197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 430 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K4	NM_005922.4	MANE Select	c.190C>T	p.Pro64Ser	missense	Exon 2 of 27	NP_005913.3	Q9Y6R4-1
	MAP3K4	NM_001301072.2		c.190C>T	p.Pro64Ser	missense	Exon 2 of 27	NP_001288001.2	F5H538
	MAP3K4	NM_006724.4		c.190C>T	p.Pro64Ser	missense	Exon 2 of 26	NP_006715.3	Q9Y6R4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K4	ENST00000392142.9	TSL:1 MANE Select	c.190C>T	p.Pro64Ser	missense	Exon 2 of 27	ENSP00000375986.4	Q9Y6R4-1
	MAP3K4	ENST00000366919.6	TSL:1	c.190C>T	p.Pro64Ser	missense	Exon 2 of 26	ENSP00000355886.2	Q9Y6R4-2
	MAP3K4	ENST00000490904.6	TSL:1	n.190C>T		non_coding_transcript_exon	Exon 2 of 28	ENSP00000446303.1	F5H1X6

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000824 AC: 207 AN: 251082 AF XY: 0.000567

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000328 AC: 479 AN: 1461544 Hom.: 2 Cov.: 31 AF XY: 0.000267 AC XY: 194 AN XY: 727076

African (AFR) AF: 0.0111 AC: 370 AN: 33470

American (AMR) AF: 0.000626 AC: 28 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111780

Other (OTH) AF: 0.000745 AC: 45 AN: 60380

GnomAD4 genome AF: 0.00282 AC: 430 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74440

African (AFR) AF: 0.00994 AC: 413 AN: 41534

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.00343

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000997 AC: 121

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.1
DANN	Benign	0.18
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N
PhyloP100		1.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.11
Sift	Benign	0.67	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.16
MPC		0.29
ClinPred		0.00019	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.024
gMVP		0.072
Mutation Taster		=98/2	polymorphism

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: rs147981479; hg19: chr6-161455328; COSMIC: COSV62333014;