chr22-21772887-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP5_Moderate
The NM_002745.5(MAPK1):c.952G>A(p.Asp318Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D318G) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
MAPK1
NM_002745.5 missense
NM_002745.5 missense
Scores
7
6
5
Clinical Significance
Conservation
PhyloP100: 7.86
Genes affected
MAPK1 (HGNC:6871): (mitogen-activated protein kinase 1) This gene encodes a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), 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. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. One study also suggests that this protein acts as a transcriptional repressor independent of its kinase activity. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_002745.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr22-21772886-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 917746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, MAPK1
PP5
?
Variant 22-21772887-C-T is Pathogenic according to our data. Variant chr22-21772887-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 917745.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-21772887-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAPK1 | NM_002745.5 | c.952G>A | p.Asp318Asn | missense_variant | 7/9 | ENST00000215832.11 | |
MAPK1 | NM_138957.3 | c.952G>A | p.Asp318Asn | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAPK1 | ENST00000215832.11 | c.952G>A | p.Asp318Asn | missense_variant | 7/9 | 1 | NM_002745.5 | P1 | |
MAPK1 | ENST00000398822.7 | c.952G>A | p.Asp318Asn | missense_variant | 7/8 | 1 | P1 | ||
MAPK1 | ENST00000544786.1 | c.820G>A | p.Asp274Asn | missense_variant | 6/7 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Atypical behavior;C0424503:Abnormal facial shape;C3714756:Intellectual disability;C4025790:Specific learning disability;CN130023:Heart, malformation of Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital | Apr 01, 2020 | - - |
Noonan syndrome 13 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 09, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
T;T;T
Polyphen
D;D;.
Vest4
MutPred
Loss of phosphorylation at S320 (P = 0.0917);Loss of phosphorylation at S320 (P = 0.0917);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at