17-12020929-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003010.4(MAP2K4):​c.43G>T​(p.Gly15Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000938 in 1,065,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G15S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: MAP2K4 NM_003010.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3099869).

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>T	p.Gly15Cys	missense	Exon 1 of 11	NP_003001.1	P45985-1
	MAP2K4	NM_001281435.2		c.43G>T	p.Gly15Cys	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>T	p.Gly15Cys	missense	Exon 1 of 11	ENSP00000262445.5	P45985-1
	MAP2K4	ENST00000415385.7	TSL:2	c.43G>T	p.Gly15Cys	missense	Exon 1 of 12	ENSP00000410402.3	P45985-2
	MAP2K4	ENST00000905332.1		c.43G>T	p.Gly15Cys	missense	Exon 1 of 11	ENSP00000575391.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.38e-7 AC: 1 AN: 1065568 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 503352

African (AFR) AF: 0.00 AC: 0 AN: 22268

American (AMR) AF: 0.00 AC: 0 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: 0.0000516 AC: 1 AN: 19390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2828

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 911012

Other (OTH) AF: 0.00 AC: 0 AN: 42496

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.082
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.13	B
Vest4		0.37
MutPred		0.34		Loss of catalytic residue at G13 (P = 0.4881)
MVP		0.87
MPC		1.3
ClinPred		0.68	D
GERP RS		3.1
PromoterAI		-0.091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.14
gMVP		0.21
Mutation Taster		=84/16	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;