chr4-127890181-C-A

Variant names:

• chr4-127890181-C-A
• rs141081905
• NM_014264.5:c.1775C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014264.5(PLK4):​c.1775C>A​(p.Ser592Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S592F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLK4 NM_014264.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25256082).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK4	NM_014264.5	MANE Select	c.1775C>A	p.Ser592Tyr	missense	Exon 7 of 16	NP_055079.3
	PLK4	NM_001441357.1		c.1778C>A	p.Ser593Tyr	missense	Exon 7 of 16	NP_001428286.1
	PLK4	NM_001190799.2		c.1679C>A	p.Ser560Tyr	missense	Exon 6 of 15	NP_001177728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK4	ENST00000270861.10	TSL:1 MANE Select	c.1775C>A	p.Ser592Tyr	missense	Exon 7 of 16	ENSP00000270861.5
	PLK4	ENST00000513090.5	TSL:2	c.1679C>A	p.Ser560Tyr	missense	Exon 6 of 15	ENSP00000427554.1
	PLK4	ENST00000514379.5	TSL:2	c.1652C>A	p.Ser551Tyr	missense	Exon 7 of 16	ENSP00000423582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.40		Loss of disorder (P = 0.0196)
MVP		0.40
MPC		0.45
ClinPred		0.98	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.11
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs141081905; hg19: chr4-128811336;