rs115701891

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025009.5(CEP135):c.1675G>A(p.Ala559Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,597,440 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 29 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 27 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.577

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:

ENSG00000299857 (HGNC:):

ENSG00000299857 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023153126).

BP6

Variant 4-55981275-G-A is Benign according to our data. Variant chr4-55981275-G-A is described in ClinVar as Benign. ClinVar VariationId is 128694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1605/152090) while in subpopulation AFR AF = 0.0371 (1537/41476). AF 95% confidence interval is 0.0355. There are 29 homozygotes in GnomAd4. There are 764 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP135	NM_025009.5 link	c.1675G>A	p.Ala559Thr	missense_variant	Exon 13 of 26	ENST00000257287.5	NP_079285.2	Q66GS9-1
CEP135	XM_006714055.4 link	c.1642G>A	p.Ala548Thr	missense_variant	Exon 13 of 26		XP_006714118.1
CEP135	XM_005265788.5 link	c.604G>A	p.Ala202Thr	missense_variant	Exon 6 of 19		XP_005265845.1
CEP135	XM_011534412.2 link	c.145G>A	p.Ala49Thr	missense_variant	Exon 3 of 16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEP135	ENST00000257287.5 link	c.1675G>A	p.Ala559Thr	missense_variant	Exon 13 of 26	1	NM_025009.5	ENSP00000257287.3	Q66GS9-1
CEP135	ENST00000506202.1 link	n.1625G>A		non_coding_transcript_exon_variant	Exon 6 of 19	1
ENSG00000299857	ENST00000766957.1 link	n.108-5193C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1605

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0372

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00315

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00269

AC:

634

AN:

235322

AF XY:

0.00198

show subpopulations

Gnomad AFR exome

AF:

0.0394

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000643

Gnomad OTH exome

AF:

0.000894

GnomAD4 exome

AF:

0.00102

AC:

1470

AN:

1445350

Hom.:

Cov.:

AF XY:

0.000892

AC XY:

641

AN XY:

718268

show subpopulations

African (AFR)

AF:

0.0394

AC:

1268

AN:

32178

American (AMR)

AF:

0.00108

AC:

AN:

41586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25880

East Asian (EAS)

AF:

0.00

AC:

AN:

38620

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1106622

Other (OTH)

AF:

0.00209

AC:

125

AN:

59710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0106

AC:

1605

AN:

152090

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

764

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0371

AC:

1537

AN:

41476

American (AMR)

AF:

0.00314

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68012

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00404

Hom.:

Bravo

AF:

0.0119

ESP6500AA

AF:

0.0399

AC:

176

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00360

AC:

437

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 03, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.5

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.0037

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

-0.58

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.23

REVEL

Benign

0.013

Sift

Benign

0.69

Sift4G

Benign

0.33

Polyphen

0.16

Vest4

0.065

MVP

0.20

MPC

0.057

ClinPred

0.0034

GERP RS

0.56

Varity_R

0.028

gMVP

0.051

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over