NM_002745.5:c.868T>G

Variant names:

• chr22-21772971-A-C
• rs147414870
• NM_002745.5:c.868T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_002745.5(MAPK1):​c.868T>G​(p.Leu290Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAPK1 NM_002745.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.998

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.868T>G	p.Leu290Val	missense_variant	Exon 7 of 9	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.868T>G	p.Leu290Val	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.868T>G	p.Leu290Val	missense_variant	Exon 7 of 9	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.868T>G	p.Leu290Val	missense_variant	Exon 7 of 8	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.736T>G	p.Leu246Val	missense_variant	Exon 6 of 7	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251478 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459296 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Benign	0.0082
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.077	T;T;T
Sift4G	Benign	0.072	T;T;T
Polyphen		0.59	P;P;.
Vest4		0.80
MutPred		0.57		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;
MVP		0.81
MPC		2.1
ClinPred		0.82	D
GERP RS		2.9
Varity_R		0.80
gMVP		0.92

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: rs147414870; hg19: chr22-22127260;