22-21799100-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_002745.5(MAPK1):c.521C>T(p.Ala174Val) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPK1 NM_002745.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a domain Protein kinase (size 288) in uniprot entity MK01_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_002745.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MAPK1
• PP5: Variant 22-21799100-G-A is Pathogenic according to our data. Variant chr22-21799100-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 917744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-21799100-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK1	NM_002745.5	c.521C>T	p.Ala174Val	missense_variant	4/9	ENST00000215832.11
MAPK1	NM_138957.3	c.521C>T	p.Ala174Val	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK1	ENST00000215832.11	c.521C>T	p.Ala174Val	missense_variant	4/9	1	NM_002745.5	P1
MAPK1	ENST00000398822.7	c.521C>T	p.Ala174Val	missense_variant	4/8	1		P1
MAPK1	ENST00000544786.1	c.521C>T	p.Ala174Val	missense_variant	4/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atypical behavior;C0424503:Abnormal facial shape;C2243051:Macrocephaly;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

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 917744). This missense change has been observed in individual(s) with a neurodevelopmental condition (PMID: 32721402; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 174 of the MAPK1 protein (p.Ala174Val). -

Noonan syndrome 13 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.23	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Uncertain	0.46
Sift	Benign	0.096	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.97	D;D;.
Vest4		0.65
MutPred		0.34		Loss of disorder (P = 0.0676);Loss of disorder (P = 0.0676);Loss of disorder (P = 0.0676);
MVP		0.91
MPC		1.5
ClinPred		0.92	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.80

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: rs2069052012; hg19: chr22-22153389;