NM_003010.4:c.43G>A

Variant names:

• chr17-12020929-G-A
• rs749070408
• NM_003010.4:c.43G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003010.4(MAP2K4):​c.43G>A​(p.Gly15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000838 in 1,217,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: MAP2K4 NM_003010.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 1 publications found

Genes affected

MAP2K4 (HGNC:6844): (mitogen-activated protein kinase kinase 4) This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ZNF18 (HGNC:12969): (zinc finger protein 18) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000293152 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17150974).
• BS2: High AC in GnomAd4 at 26 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003010.4. 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
	MAP2K4	NM_003010.4	MANE Select	c.43G>A	p.Gly15Ser	missense	Exon 1 of 11	NP_003001.1	P45985-1
	MAP2K4	NM_001281435.2		c.43G>A	p.Gly15Ser	missense	Exon 1 of 12	NP_001268364.1	P45985-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K4	ENST00000353533.10	TSL:1 MANE Select	c.43G>A	p.Gly15Ser	missense	Exon 1 of 11	ENSP00000262445.5	P45985-1
	MAP2K4	ENST00000415385.7	TSL:2	c.43G>A	p.Gly15Ser	missense	Exon 1 of 12	ENSP00000410402.3	P45985-2
	MAP2K4	ENST00000905332.1		c.43G>A	p.Gly15Ser	missense	Exon 1 of 11	ENSP00000575391.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151802 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000713 AC: 76 AN: 1065568 Hom.: 0 Cov.: 32 AF XY: 0.0000656 AC XY: 33 AN XY: 503352

African (AFR) AF: 0.000269 AC: 6 AN: 22268

American (AMR) AF: 0.000764 AC: 6 AN: 7850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13562

East Asian (EAS) AF: 0.00 AC: 0 AN: 25304

South Asian (SAS) AF: 0.00 AC: 0 AN: 19390

European-Finnish (FIN) AF: 0.000288 AC: 6 AN: 20858

Middle Eastern (MID) AF: 0.000354 AC: 1 AN: 2828

European-Non Finnish (NFE) AF: 0.0000505 AC: 46 AN: 911012

Other (OTH) AF: 0.000259 AC: 11 AN: 42496

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151802 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 12 AN XY: 74136

African (AFR) AF: 0.000338 AC: 14 AN: 41390

American (AMR) AF: 0.000197 AC: 3 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.0000952 AC: 1 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000204

ExAC AF: 0.000262 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.16
Sift	Benign	0.60	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.25		Gain of phosphorylation at G15 (P = 0.0026)
MVP		0.90
MPC		1.2
ClinPred		0.44	T
GERP RS		3.1
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.049
gMVP		0.16
Mutation Taster		=83/17	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: rs749070408; hg19: chr17-11924246;