rs1433730979

Positions:

• chr11-95813588-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014679.5(CEP57):​c.503A>T​(p.Gln168Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,460,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CEP57 NM_014679.5 missense, splice_region
• Scores: Splicing: ADA: 0.3447
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60

Genes affected

CEP57 (HGNC:30794): (centrosomal protein 57) This gene encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubular stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the C-terminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein specifically interacts with fibroblast growth factor 2 (FGF2), sorting nexin 6, Ran-binding protein M and the kinesins KIF3A and KIF3B, and thus mediates the nuclear translocation and mitogenic activity of the FGF2. It also interacts with cyclin D1 and controls nucleocytoplasmic distribution of the cyclin D1 in quiescent cells. This protein is crucial for maintaining correct chromosomal number during cell division. Mutations in this gene cause mosaic variegated aneuploidy syndrome, a rare autosomal recessive disorder. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

CEP57 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP57	NM_014679.5	c.503A>T	p.Gln168Leu	missense_variant, splice_region_variant	4/11	ENST00000325542.10	NP_055494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP57	ENST00000325542.10	c.503A>T	p.Gln168Leu	missense_variant, splice_region_variant	4/11	1	NM_014679.5	ENSP00000317902.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249890 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460314 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2017

This sequence change replaces glutamine with leucine at codon 168 of the CEP57 protein (p.Gln168Leu). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and leucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CEP57-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.;T;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.8	.;M;M;.;.;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.93, 1.0, 1.0	.;P;D;.;.;D;.
Vest4		0.87
MutPred		0.73		.;Loss of MoRF binding (P = 0.1656);Loss of MoRF binding (P = 0.1656);.;.;Loss of MoRF binding (P = 0.1656);.;
MVP		0.71
MPC		0.39
ClinPred		0.98	D
GERP RS		0.43
Varity_R		0.54
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.34
dbscSNV1_RF	Benign	0.61
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: rs1433730979; hg19: chr11-95546752;