17-12129194-A-T

Variant names:

• chr17-12129194-A-T
• NM_003010.4:c.947A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003010.4(MAP2K4):​c.947A>T​(p.Gln316Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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: 9.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K4	NM_003010.4	c.947A>T	p.Gln316Leu	missense_variant	Exon 9 of 11	ENST00000353533.10	NP_003001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K4	ENST00000353533.10	c.947A>T	p.Gln316Leu	missense_variant	Exon 9 of 11	1	NM_003010.4	ENSP00000262445.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1

Jun 19, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Gln316Leu variant in MAP2K4 was identified by our study in 1 individual with a neurodevelopmental disorder. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for neurodevelopmental disorders. Given the limited information about this gene-disease relationship, the significance of the p.Gln316Leu variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in MAP2K4 we encourage you to reach out to us. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.78	N;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.97	D;D
Vest4		0.78
MutPred		0.71		Loss of disorder (P = 0.091);.;
MVP		0.88
MPC		1.3
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-12032511;