4-55965812-AAAG-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_025009.5(CEP135):c.1004_1006delAAG(p.Glu335del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 8.63

Publications

5 publications found

Variant links:

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]

CEP135 Gene-Disease associations (from GenCC):

microcephaly 8, primary, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP135 links:

LOC124900705 (HGNC:):

LOC124900705 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 210672.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025009.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	NM_025009.5	MANE Select	c.1004_1006delAAG	p.Glu335del	disruptive_inframe_deletion	Exon 8 of 26	NP_079285.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP135	ENST00000257287.5	TSL:1 MANE Select	c.1004_1006delAAG	p.Glu335del	disruptive_inframe_deletion	Exon 8 of 26	ENSP00000257287.3
CEP135	ENST00000506202.1	TSL:1	n.954_956delAAG		non_coding_transcript_exon	Exon 1 of 19
CEP135	ENST00000515081.1	TSL:2	n.638_640delAAG		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152228

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00267

AC:

670

AN:

250710

AF XY:

0.00258

show subpopulations

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 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.:

AF XY:

0.00210

AC XY:

1529

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33460

American (AMR)

AF:

0.00181

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00739

AC:

193

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86208

European-Finnish (FIN)

AF:

0.00732

AC:

391

AN:

53392

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00175

AC:

1941

AN:

1111752

Other (OTH)

AF:

0.00346

AC:

209

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

149

299

448

598

747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152346

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41578

American (AMR)

AF:

0.00176

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00631

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00237

AC:

161

AN:

68032

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000839

Hom.:

Bravo

AF:

0.00185

EpiCase

AF:

0.00245

EpiControl

AF:

0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 13, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Sep 04, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CEP135-related disorder

Benign:1

May 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.6

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over