22-21772886-T-G

Variant names:

• chr22-21772886-T-G
• NM_002745.5:c.953A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_002745.5(MAPK1):​c.953A>C​(p.Asp318Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.97

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a short_sequence_motif Cytoplasmic retention motif (size 4) in uniprot entity MK01_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 Lovd as [Pathogenic].
• PP2: Missense variant in the MAPK1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.6111 (above the threshold of 3.09). Trascript score misZ: 3.6223 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome 13.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.953A>C	p.Asp318Ala	missense_variant	Exon 7 of 9	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.953A>C	p.Asp318Ala	missense_variant	Exon 7 of 8		NP_620407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK1	ENST00000215832.11	c.953A>C	p.Asp318Ala	missense_variant	Exon 7 of 9	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.953A>C	p.Asp318Ala	missense_variant	Exon 7 of 8	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.821A>C	p.Asp274Ala	missense_variant	Exon 6 of 7	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Pathogenic	3.9	H;H;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.69
MutPred		0.62		Loss of stability (P = 0.077);Loss of stability (P = 0.077);.;
MVP		0.71
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.89

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: chr22-22127175;