rs879255691

Variant names:

• chr4-127883334-TTGAAACATCCTTC-T
• rs879255691
• NM_014264.5:c.201_213delGAAACATCCTTCT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_014264.5(PLK4):​c.201_213delGAAACATCCTTCT​(p.Lys68SerfsTer18) variant causes a frameshift 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. L67L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLK4 NM_014264.5 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.86
• Publications: 1 publications found

Genes affected

PLK4 (HGNC:11397): (polo like kinase 4) This gene encodes a member of the polo family of serine/threonine protein kinases. The protein localizes to centrioles, complex microtubule-based structures found in centrosomes, and regulates centriole duplication during the cell cycle. Three alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

PLK4 Gene-Disease associations (from GenCC):

• microcephaly and chorioretinopathy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina
• microcephaly and chorioretinopathy 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLK4	NM_014264.5	c.201_213delGAAACATCCTTCT	p.Lys68SerfsTer18	frameshift_variant	Exon 3 of 16	ENST00000270861.10	NP_055079.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLK4	ENST00000270861.10	c.201_213delGAAACATCCTTCT	p.Lys68SerfsTer18	frameshift_variant	Exon 3 of 16	1	NM_014264.5	ENSP00000270861.5

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Mar 29, 2018

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs879255691; hg19: chr4-128804489;