NM_014264.5:c.2895G>A

Variant names:

• chr4-127898523-G-A
• rs6820138
• NM_014264.5:c.2895G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014264.5(PLK4):​c.2895G>A​(p.Pro965Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,521,274 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: PLK4 NM_014264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.01
• 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: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• microcephaly and chorioretinopathy 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-127898523-G-A is Benign according to our data. Variant chr4-127898523-G-A is described in ClinVar as Benign. ClinVar VariationId is 436343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0031 (471/152100) while in subpopulation AFR AF = 0.0109 (454/41494). AF 95% confidence interval is 0.0101. There are 4 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK4	NM_014264.5	MANE Select	c.2895G>A	p.Pro965Pro	synonymous	Exon 16 of 16	NP_055079.3
	PLK4	NM_001441357.1		c.2898G>A	p.Pro966Pro	synonymous	Exon 16 of 16	NP_001428286.1
	PLK4	NM_001190799.2		c.2799G>A	p.Pro933Pro	synonymous	Exon 15 of 15	NP_001177728.1	O00444-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK4	ENST00000270861.10	TSL:1 MANE Select	c.2895G>A	p.Pro965Pro	synonymous	Exon 16 of 16	ENSP00000270861.5	O00444-1
	PLK4	ENST00000513090.5	TSL:2	c.2799G>A	p.Pro933Pro	synonymous	Exon 15 of 15	ENSP00000427554.1	O00444-2
	PLK4	ENST00000852980.1		c.2793G>A	p.Pro931Pro	synonymous	Exon 16 of 16	ENSP00000523039.1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 471 AN: 151984 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000824 AC: 199 AN: 241638 AF XY: 0.000598

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000317

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.000305 AC: 417 AN: 1369174 Hom.: 3 Cov.: 21 AF XY: 0.000258 AC XY: 177 AN XY: 685768

African (AFR) AF: 0.0105 AC: 328 AN: 31308

American (AMR) AF: 0.000427 AC: 18 AN: 42122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25442

East Asian (EAS) AF: 0.00 AC: 0 AN: 38810

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.000545 AC: 3 AN: 5508

European-Non Finnish (NFE) AF: 0.0000397 AC: 41 AN: 1034044

Other (OTH) AF: 0.000455 AC: 26 AN: 57180

GnomAD4 genome AF: 0.00310 AC: 471 AN: 152100 Hom.: 4 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74346

African (AFR) AF: 0.0109 AC: 454 AN: 41494

American (AMR) AF: 0.00105 AC: 16 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00190 Hom.: 1

Bravo AF: 0.00359

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.2
DANN	Benign	0.33
PhyloP100		3.0

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: rs6820138; hg19: chr4-128819678;