Genetic Variant MAP2K4:p.Pro27Gln (chr17-12020966-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003010.4(MAP2K4):c.80C>A(p.Pro27Gln) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAP2K4
NM_003010.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69

Publications

0 publications found

Variant links:

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]

MAP2K4 links:

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]

ZNF18 links:

ENSG00000293152 (HGNC:):

ENSG00000293152 links:

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ACMG classification

Classification was made for transcript

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=0.1325002).

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.80C>A	p.Pro27Gln	missense	Exon 1 of 11	NP_003001.1	P45985-1
	MAP2K4	NM_001281435.2		c.80C>A	p.Pro27Gln	missense	Exon 1 of 12	NP_001268364.1	P45985-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP2K4	ENST00000353533.10	TSL:1 MANE Select	c.80C>A	p.Pro27Gln	missense	Exon 1 of 11	ENSP00000262445.5	P45985-1
MAP2K4	ENST00000415385.7	TSL:2	c.80C>A	p.Pro27Gln	missense	Exon 1 of 12	ENSP00000410402.3	P45985-2
MAP2K4	ENST00000905332.1		c.80C>A	p.Pro27Gln	missense	Exon 1 of 11	ENSP00000575391.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1062746

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

501842

African (AFR)

AF:

0.00

AC:

AN:

22194

American (AMR)

AF:

0.00

AC:

AN:

7768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13448

East Asian (EAS)

AF:

0.00

AC:

AN:

24966

South Asian (SAS)

AF:

0.00

AC:

AN:

19380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2822

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

909060

Other (OTH)

AF:

0.00

AC:

AN:

42306

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

PhyloP100

1.7

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.27

REVEL

Benign

0.12

Sift

Benign

0.71

Sift4G

Benign

0.23

Polyphen

0.56

Vest4

0.27

MutPred

0.21

Gain of catalytic residue at P27 (P = 0.0794)

MVP

0.74

MPC

1.1

ClinPred

0.19

GERP RS

3.1

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.067

gMVP

0.29

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over