10-48409799-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001323329.2(MAPK8):c.253-80T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0993 in 920,064 control chromosomes in the GnomAD database, including 5,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1131 hom., cov: 32)
  • Exomes 𝑓: 0.098 (4809 hom.)
• Consequence: MAPK8 NM_001323329.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.162

Genes affected

MAPK8 (HGNC:6881): (mitogen-activated protein kinase 8) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases 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. This kinase is activated by various cell stimuli, and targets specific transcription factors, and thus mediates immediate-early gene expression in response to cell stimuli. The activation of this kinase by tumor-necrosis factor alpha (TNF-alpha) is found to be required for TNF-alpha induced apoptosis. This kinase is also involved in UV radiation induced apoptosis, which is thought to be related to cytochrom c-mediated cell death pathway. Studies of the mouse counterpart of this gene suggested that this kinase play a key role in T cell proliferation, apoptosis and differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 10-48409799-T-A is Benign according to our data. Variant chr10-48409799-T-A is described in ClinVar as [Benign]. Clinvar id is 1260927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8	NM_001323329.2	c.253-80T>A		intron_variant		ENST00000374189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8	ENST00000374189.6	c.253-80T>A		intron_variant		5	NM_001323329.2	A1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16042 AN: 152140 Hom.: 1132 Cov.: 32

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0751

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.0981 AC: 75302 AN: 767806 Hom.: 4809 AF XY: 0.101 AC XY: 40246 AN XY: 400158

Gnomad4 AFR exome AF: 0.0901

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.0155

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.0810

Gnomad4 NFE exome AF: 0.0871

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.105 AC: 16063 AN: 152258 Hom.: 1131 Cov.: 32 AF XY: 0.108 AC XY: 8069 AN XY: 74446

Gnomad4 AFR AF: 0.0950

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0277

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.0751

Gnomad4 NFE AF: 0.0858

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0980 Hom.: 114

Bravo AF: 0.114

Asia WGS AF: 0.129 AC: 447 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied by a panel of primary immunodeficiencies. Number of patients: 38. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	2.8
Dann	Benign	0.81

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: rs3730157; hg19: chr10-49617842;