22-21805852-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_002745.5(MAPK1):c.490A>C(p.Lys164Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAPK1 NM_002745.5 missense, splice_region
• Scores: Splicing: ADA: 0.6378
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK1	NM_002745.5	c.490A>C	p.Lys164Gln	missense_variant, splice_region_variant	3/9	ENST00000215832.11
MAPK1	NM_138957.3	c.490A>C	p.Lys164Gln	missense_variant, splice_region_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK1	ENST00000215832.11	c.490A>C	p.Lys164Gln	missense_variant, splice_region_variant	3/9	1	NM_002745.5	P1
MAPK1	ENST00000398822.7	c.490A>C	p.Lys164Gln	missense_variant, splice_region_variant	3/8	1		P1
MAPK1	ENST00000544786.1	c.490A>C	p.Lys164Gln	missense_variant, splice_region_variant	3/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000824 AC: 119 AN: 1444906 Hom.: 0 Cov.: 30 AF XY: 0.0000668 AC XY: 48 AN XY: 718988

Gnomad4 AFR exome AF: 0.0000917

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0000356

Gnomad4 FIN exome AF: 0.0000944

Gnomad4 NFE exome AF: 0.0000915

Gnomad4 OTH exome AF: 0.0000670

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.490A>C (p.K164Q) alteration is located in exon 3 (coding exon 3) of the MAPK1 gene. This alteration results from a A to C substitution at nucleotide position 490, causing the lysine (K) at amino acid position 164 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	2.9	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.85		Loss of ubiquitination at K164 (P = 0.0183);Loss of ubiquitination at K164 (P = 0.0183);Loss of ubiquitination at K164 (P = 0.0183);
MVP		0.97
MPC		2.6
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.64
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.090		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: chr22-22160141;