12-111842750-A-G

Position:

• chr12-111842750-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003668.4(MAPKAPK5):​c.17A>G​(p.Asp6Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000835 in 1,198,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: MAPKAPK5 NM_003668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

Genes affected

MAPKAPK5 (HGNC:6889): (MAPK activated protein kinase 5) The protein encoded by this gene is a tumor suppressor and member of the serine/threonine kinase family. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. The encoded protein is found in the nucleus but translocates to the cytoplasm upon phosphorylation and activation. This kinase phosphorylates heat shock protein HSP27 at its physiologically relevant sites. Two alternately spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2012]

MAPKAPK5-AS1 (HGNC:24091): (MAPKAPK5 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16480595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPKAPK5	NM_003668.4	c.17A>G	p.Asp6Gly	missense_variant	1/14	ENST00000550735.7
MAPKAPK5-AS1	NR_015404.2	n.256T>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPKAPK5	ENST00000550735.7	c.17A>G	p.Asp6Gly	missense_variant	1/14	1	NM_003668.4	P4
MAPKAPK5-AS1	ENST00000428207.4	n.153T>C		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1198190 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 580584

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: 0.00000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 09, 2022

The c.17A>G (p.D6G) alteration is located in exon 1 (coding exon 1) of the MAPKAPK5 gene. This alteration results from a A to G substitution at nucleotide position 17, causing the aspartic acid (D) at amino acid position 6 to be replaced by a glycine (G). 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	0.079
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;.;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N;.;N;.
MutationTaster	Benign	0.81	N;N;N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.61	N;.;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.026	D;.;D;.
Sift4G	Benign	0.26	T;.;T;D
Polyphen		0.0	B;.;B;.
Vest4		0.35
MutPred		0.18		Gain of glycosylation at S5 (P = 0.0183);Gain of glycosylation at S5 (P = 0.0183);Gain of glycosylation at S5 (P = 0.0183);Gain of glycosylation at S5 (P = 0.0183);
MVP		0.67
MPC		0.71
ClinPred		0.34	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112280554;