rs724159995

Variant names:

• chr4-127898434-C-G
• rs724159995
• NM_014264.5:c.2811-5C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_014264.5(PLK4):​c.2811-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLK4 NM_014264.5 splice_region, intron
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.161
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-127898434-C-G is Pathogenic according to our data. Variant chr4-127898434-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 162400.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLK4	NM_014264.5	c.2811-5C>G		splice_region_variant, intron_variant	Intron 15 of 15	ENST00000270861.10	NP_055079.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLK4	ENST00000270861.10	c.2811-5C>G		splice_region_variant, intron_variant	Intron 15 of 15	1	NM_014264.5	ENSP00000270861.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1183826 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 601748

African (AFR) AF: 0.00 AC: 0 AN: 27588

American (AMR) AF: 0.00 AC: 0 AN: 38220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24096

East Asian (EAS) AF: 0.00 AC: 0 AN: 37992

South Asian (SAS) AF: 0.00 AC: 0 AN: 76234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 870228

Other (OTH) AF: 0.00 AC: 0 AN: 51074

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microcephaly and chorioretinopathy 2 Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.88
PhyloP100		0.16
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: 1
DS_AL_spliceai		0.31		Position offset: 5

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

Other links and lift over

dbSNP: rs724159995; hg19: chr4-128819589;