chr5-75677821-G-A

Variant names:

• chr5-75677821-G-A
• rs771564291
• NM_001099271.2:c.1537C>T

Variant summary

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

The NM_001099271.2(POC5):​c.1537C>T​(p.Pro513Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P513L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: POC5 NM_001099271.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

Genes affected

POC5 (HGNC:26658): (POC5 centriolar protein) Predicted to enable identical protein binding activity. Located in centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ANKDD1B (HGNC:32525): (ankyrin repeat and death domain containing 1B) Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POC5	NM_001099271.2	c.1537C>T	p.Pro513Ser	missense_variant	Exon 11 of 12	ENST00000428202.7	NP_001092741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POC5	ENST00000428202.7	c.1537C>T	p.Pro513Ser	missense_variant	Exon 11 of 12	1	NM_001099271.2	ENSP00000410216.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000405 AC: 10 AN: 247038 AF XY: 0.0000596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000804

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460148 Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23 AN XY: 726396

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33358

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44540

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26104

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39588

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86020

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53328

Gnomad4 NFE exome AF: 0.0000225 AC: 25 AN: 1111130

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60318

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74296

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588218 AN: 0.0000588218

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.000110

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 513 of the POC5 protein (p.Pro513Ser). This variant is present in population databases (rs771564291, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POC5-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.80
MutPred		0.47		Gain of phosphorylation at P513 (P = 0.0385);.;.;
MVP		0.88
MPC		0.37
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.73
gMVP		0.60
Mutation Taster		=48/52	disease causing

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

Publications

LitVar

Other links and lift over

dbSNP: rs771564291; hg19: chr5-74973646; COSMIC: COSV66842773;