6-160992019-C-A

Variant names:

• chr6-160992019-C-A
• rs771440561
• NM_005922.4:c.88C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005922.4(MAP3K4):​c.88C>A​(p.Pro30Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAP3K4 NM_005922.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.880
• Publications: 0 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]

MAP3K4-AS1 (HGNC:55048): (MAP3K4 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16637969).

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.88C>A	p.Pro30Thr	missense	Exon 1 of 27	NP_005913.3	Q9Y6R4-1
	MAP3K4	NM_001301072.2		c.88C>A	p.Pro30Thr	missense	Exon 1 of 27	NP_001288001.2	F5H538
	MAP3K4	NM_006724.4		c.88C>A	p.Pro30Thr	missense	Exon 1 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.88C>A	p.Pro30Thr	missense	Exon 1 of 27	ENSP00000375986.4	Q9Y6R4-1
	MAP3K4	ENST00000366919.6	TSL:1	c.88C>A	p.Pro30Thr	missense	Exon 1 of 26	ENSP00000355886.2	Q9Y6R4-2
	MAP3K4	ENST00000490904.6	TSL:1	n.88C>A		non_coding_transcript_exon	Exon 1 of 28	ENSP00000446303.1	F5H1X6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402860 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 694572

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30604

American (AMR) AF: 0.00 AC: 0 AN: 38672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 35454

South Asian (SAS) AF: 0.00 AC: 0 AN: 80332

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089522

Other (OTH) AF: 0.00 AC: 0 AN: 58488

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	16
DANN	Benign	0.54
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.88
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.94	P
Vest4		0.29
MutPred		0.38		Gain of phosphorylation at P30 (P = 0)
MVP		0.60
MPC		0.32
ClinPred		0.30	T
GERP RS		0.12
PromoterAI		0.038	Neutral
Varity_R		0.22
gMVP		0.087
Mutation Taster		=97/3	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: rs771440561; hg19: chr6-161413051;