17-12020912-G-A

Variant names:

• chr17-12020912-G-A
• rs989028622
• NM_003010.4:c.26G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003010.4(MAP2K4):​c.26G>A​(p.Gly9Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP2K4 NM_003010.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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]

RPL21P122 (HGNC:36990): (ribosomal protein L21 pseudogene 122)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30650306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K4	NM_003010.4	c.26G>A	p.Gly9Asp	missense_variant	Exon 1 of 11	ENST00000353533.10	NP_003001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K4	ENST00000353533.10	c.26G>A	p.Gly9Asp	missense_variant	Exon 1 of 11	1	NM_003010.4	ENSP00000262445.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26G>A (p.G9D) alteration is located in exon 1 (coding exon 1) of the MAP2K4 gene. This alteration results from a G to A substitution at nucleotide position 26, causing the glycine (G) at amino acid position 9 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.27
Sift	Benign	0.18	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.0	B;D
Vest4		0.39
MutPred		0.21		Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);
MVP		0.88
MPC		1.5
ClinPred		0.81	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.16
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs989028622; hg19: chr17-11924229;