12-111868788-GG-TC

Variant names:

• chr12-111868788-GG-TC
• NM_003668.4:c.320_321delGGinsTC
• MAPKAPK5 p.Gly107Val

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_003668.4(MAPKAPK5):​c.320_321delGGinsTC​(p.Gly107Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPKAPK5 NM_003668.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.96
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurocardiofaciodigital syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_003668.4 (MAPKAPK5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003668.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK5	NM_003668.4	MANE Select	c.320_321delGGinsTC	p.Gly107Val	missense	N/A	NP_003659.2
	MAPKAPK5	NM_001371479.1		c.320_321delGGinsTC	p.Gly107Val	missense	N/A	NP_001358408.1
	MAPKAPK5	NM_001371480.1		c.320_321delGGinsTC	p.Gly107Val	missense	N/A	NP_001358409.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK5	ENST00000550735.7	TSL:1 MANE Select	c.320_321delGGinsTC	p.Gly107Val	missense	N/A	ENSP00000449667.2	Q8IW41-2
	MAPKAPK5	ENST00000551404.7	TSL:5	c.320_321delGGinsTC	p.Gly107Val	missense	N/A	ENSP00000449381.2	Q8IW41-1
	MAPKAPK5	ENST00000549875.1	TSL:5	c.37-2297_37-2296delGGinsTC		intron	N/A	ENSP00000473467.1	R4GN33

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-112306592;