rs374626758

chr4-55965812-AAAG-Achr4-55965812-AAAG-AAAGAAG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_025009.5(CEP135):c.1004_1006del(p.Glu335del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,613,760 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (12 hom.)
• Consequence: CEP135 NM_025009.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 8.63

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]

LOC124900705 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_025009.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 4-55965812-AAAG-A is Benign according to our data. Variant chr4-55965812-AAAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210672.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00209 (318/152346) while in subpopulation NFE AF= 0.00237 (161/68032). AF 95% confidence interval is 0.00207. There are 1 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5	c.1004_1006del	p.Glu335del	inframe_deletion	8/26	ENST00000257287.5
LOC124900705	XR_007058124.1	n.197+4958_197+4960del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5	c.1004_1006del	p.Glu335del	inframe_deletion	8/26	1	NM_025009.5	P1
CEP135	ENST00000506202.1	n.954_956del		non_coding_transcript_exon_variant	1/19	1
CEP135	ENST00000515081.1	n.638_640del		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00267 AC: 670 AN: 250710 Hom.: 2 AF XY: 0.00258 AC XY: 350 AN XY: 135584

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.00698

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00210 AC: 3063 AN: 1461414 Hom.: 12 AF XY: 0.00210 AC XY: 1529 AN XY: 726996

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00739

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.00732

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74492

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.000839 Hom.: 0

Bravo AF: 0.00185

EpiCase AF: 0.00245

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 04, 2014

- -

CEP135-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs374626758; hg19: chr4-56831978;