dbSNP rs147414870: MAPK1:p.Leu290Val (chr22-21772971-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.998

Variant links:

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]

MAPK1 links:

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ACMG classification

Classification made for transcript

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 link	c.868T>G	p.Leu290Val	missense_variant	Exon 7 of 9	ENST00000215832.11	NP_002736.3	P28482-1Q1HBJ4Q499G7
MAPK1	NM_138957.3 link	c.868T>G	p.Leu290Val	missense_variant	Exon 7 of 8		NP_620407.1	P28482-1Q1HBJ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAPK1	ENST00000215832.11 link	c.868T>G	p.Leu290Val	missense_variant	Exon 7 of 9	1	NM_002745.5	ENSP00000215832.7	P28482-1
MAPK1	ENST00000398822.7 link	c.868T>G	p.Leu290Val	missense_variant	Exon 7 of 8	1		ENSP00000381803.3	P28482-1
MAPK1	ENST00000544786.1 link	c.736T>G	p.Leu246Val	missense_variant	Exon 6 of 7	1		ENSP00000440842.1	P28482-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251478

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

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:

AN:

1459296

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726198

show subpopulations

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.:

ExAC

AF:

0.00000824

AC:

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

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;T;.

Eigen

Benign

0.0082

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Pathogenic

0.86

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over