chr4-86194382-T-C

Position:

• chr4-86194382-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138980.4(MAPK10):​c.-122A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000685 in 1,459,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAPK10 NM_138980.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

Genes affected

MAPK10 (HGNC:6872): (mitogen-activated protein kinase 10) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as integration points for multiple biochemical signals, and thus are involved in a wide variety of cellular processes, such as proliferation, differentiation, transcription regulation and development. This kinase is specifically expressed in a subset of neurons in the nervous system, and is activated by threonine and tyrosine phosphorylation. Targeted deletion of this gene in mice suggests that it may have a role in stress-induced neuronal apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

MAPK10-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31773633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK10	NM_138982.4	c.20A>G	p.Tyr7Cys	missense_variant	3/14	ENST00000641462.2	NP_620448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK10	ENST00000641462.2	c.20A>G	p.Tyr7Cys	missense_variant	3/14		NM_138982.4	ENSP00000493435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250220 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135216

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: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459120 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726092

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.20A>G (p.Y7C) alteration is located in exon 3 (coding exon 1) of the MAPK10 gene. This alteration results from a A to G substitution at nucleotide position 20, causing the tyrosine (Y) at amino acid position 7 to be replaced by a cysteine (C). 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	Benign	0.074
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.27	.;.;T;T;T;T;T;T;T;.;.;T;.;.;.;T;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;T;T;.;.;.;.;.;T;T;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	0.054
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;D;.;D;D;.;.;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.0	.;.;N;N;N;N;N;N;N;.;.;N;.;N;.;N;N;.;N;N;N;.;.;N;N;N;.;.;N;.;.;N;N;.;N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.23	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;N;N;.;.;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;D;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.42, 0.55	.;.;B;B;B;B;B;B;B;.;.;B;.;P;.;B;P;.;P;B;P;.;.;B;P;P;.;.;P;.;.;B;P;.;P;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.53
MutPred		0.43		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.71
ClinPred		0.34	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.72

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: rs1286031922; hg19: chr4-87115535;