chr5-180238338-G-T

Position:

• chr5-180238338-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_002752.5(MAPK9):​c.1126C>A​(p.Pro376Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MAPK9 NM_002752.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.917

Genes affected

MAPK9 (HGNC:6886): (mitogen-activated protein kinase 9) 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 targets specific transcription factors, and thus mediates immediate-early gene expression in response to various cell stimuli. It is most closely related to MAPK8, both of which are involved in UV radiation induced apoptosis, thought to be related to the cytochrome c-mediated cell death pathway. This gene and MAPK8 are also known as c-Jun N-terminal kinases. This kinase blocks the ubiquitination of tumor suppressor p53, and thus it increases the stability of p53 in nonstressed cells. Studies of this gene's mouse counterpart suggest a key role in T-cell differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1431607).
• BP6: Variant 5-180238338-G-T is Benign according to our data. Variant chr5-180238338-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2546242.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK9	NM_002752.5	c.1126C>A	p.Pro376Thr	missense_variant	11/12	ENST00000452135.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK9	ENST00000452135.7	c.1126C>A	p.Pro376Thr	missense_variant	11/12	5	NM_002752.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458790 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 725908

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Uncertain	0.63	D;.;.;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.86	D;T;D;T;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.9	L;L;L;L;.
MutationTaster	Benign	0.96	D;D;D;D;D;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.11	T;T;T;T;T
Sift4G	Benign	0.083	T;D;T;D;T
Polyphen		0.29	B;B;P;B;.
Vest4		0.27
MutPred		0.21		Gain of phosphorylation at P376 (P = 0.027);Gain of phosphorylation at P376 (P = 0.027);Gain of phosphorylation at P376 (P = 0.027);Gain of phosphorylation at P376 (P = 0.027);.;
MVP		0.65
MPC		0.64
ClinPred		0.32	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1757353147; hg19: chr5-179665338;