rs1553895368

chr4-56017774-CTT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_025009.5(CEP135):c.2930_2931del(p.Leu977GlnfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CEP135 NM_025009.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.74

Genes affected

CEP135 (HGNC:29086): (centrosomal protein 135) This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Mutations in this gene are associated with autosomal recessive primary microcephaly-8. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-56017774-CTT-C is Pathogenic according to our data. Variant chr4-56017774-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 433185.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5	c.2930_2931del	p.Leu977GlnfsTer6	frameshift_variant	22/26	ENST00000257287.5
CEP135	XM_005265788.5	c.1859_1860del	p.Leu620GlnfsTer6	frameshift_variant	15/19
CEP135	XM_006714055.4	c.2897_2898del	p.Leu966GlnfsTer6	frameshift_variant	22/26
CEP135	XM_011534412.2	c.1400_1401del	p.Leu467GlnfsTer6	frameshift_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5	c.2930_2931del	p.Leu977GlnfsTer6	frameshift_variant	22/26	1	NM_025009.5	P1
CEP135	ENST00000506202.1	n.2880_2881del		non_coding_transcript_exon_variant	15/19	1
CEP135	ENST00000706801.1	n.995_996del		non_coding_transcript_exon_variant	6/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461568 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 8, primary, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

May 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs1553895368; hg19: chr4-56883940;