chr7-40133202-A-TCC

Position:

• chr7-40133202-A-TCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_138701.4(MPLKIP):​c.397delinsGGA​(p.Ser133GlyfsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MPLKIP NM_138701.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.96

Genes affected

MPLKIP (HGNC:16002): (M-phase specific PLK1 interacting protein) The protein encoded by this gene localizes to the centrosome during mitosis and to the midbody during cytokinesis. The protein is phosphorylated by cyclin-dependent kinase 1 during mitosis and subsequently interacts with polo-like kinase 1. The protein is thought to function in regulating mitosis and cytokinesis. Mutations in this gene result in nonphotosensitive trichothiodystrophy. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-40133202-A-TCC is Pathogenic according to our data. Variant chr7-40133202-A-TCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3242125.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPLKIP	NM_138701.4	c.397delinsGGA	p.Ser133GlyfsTer21	frameshift_variant	2/2	ENST00000306984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPLKIP	ENST00000306984.8	c.397delinsGGA	p.Ser133GlyfsTer21	frameshift_variant	2/2	1	NM_138701.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Trichothiodystrophy 4, nonphotosensitive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

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The observed frameshift variant c.397delTinsGGA (p.Ser133GlyfsTer21) in the MPLKIP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is absent in gnomAD Exomes database. This variant has not been submitted to the ClinVar database. This variant causes a frameshift starting with codon Serine 133, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 21 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in MPLKIP gene have been previously reported to be disease causing (Botta E, et al. 2007). A downstream frameshift pathogenic variant has previously been reported to be pathogenic (Pode-Shakked et al. 2015). However, since this variant is present in the last exon, additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr7-40172801;