rs77591659

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.335G>A(p.Arg112His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,600,192 control chromosomes in the GnomAD database, including 1,177 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 69 hom., cov: 33)

Exomes 𝑓: 0.036 ( 1108 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.08

Publications

15 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016501546).

BP6

Variant 4-55954246-G-A is Benign according to our data. Variant chr4-55954246-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.027 (4115/152276) while in subpopulation NFE AF = 0.0416 (2832/68012). AF 95% confidence interval is 0.0404. There are 69 homozygotes in GnomAd4. There are 1919 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 69 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	NM_025009.5	MANE Select	c.335G>A	p.Arg112His	missense	Exon 4 of 26	NP_079285.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CEP135	ENST00000257287.5	TSL:1 MANE Select	c.335G>A	p.Arg112His	missense	Exon 4 of 26	ENSP00000257287.3	Q66GS9-1
CEP135	ENST00000916105.1		c.335G>A	p.Arg112His	missense	Exon 4 of 27	ENSP00000586164.1
CEP135	ENST00000916104.1		c.335G>A	p.Arg112His	missense	Exon 4 of 26	ENSP00000586163.1

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4117

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00830

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0255

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00745

Gnomad FIN

AF:

0.0310

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0297

GnomAD2 exomes

AF:

0.0285

AC:

6877

AN:

241070

AF XY:

0.0294

show subpopulations

Gnomad AFR exome

AF:

0.00696

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0324

Gnomad NFE exome

AF:

0.0436

Gnomad OTH exome

AF:

0.0321

GnomAD4 exome

AF:

0.0362

AC:

52408

AN:

1447916

Hom.:

1108

Cov.:

AF XY:

0.0357

AC XY:

25695

AN XY:

719994

show subpopulations

African (AFR)

AF:

0.00621

AC:

204

AN:

32848

American (AMR)

AF:

0.0169

AC:

717

AN:

42320

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

751

AN:

25820

East Asian (EAS)

AF:

0.0000769

AC:

AN:

39008

South Asian (SAS)

AF:

0.00946

AC:

787

AN:

83222

European-Finnish (FIN)

AF:

0.0324

AC:

1724

AN:

53178

Middle Eastern (MID)

AF:

0.0363

AC:

207

AN:

5700

European-Non Finnish (NFE)

AF:

0.0416

AC:

46009

AN:

1106078

Other (OTH)

AF:

0.0336

AC:

2006

AN:

59742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2216

4432

6648

8864

11080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1664

3328

4992

6656

8320

<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:

0.0270

AC:

4115

AN:

152276

Hom.:

Cov.:

AF XY:

0.0258

AC XY:

1919

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00828

AC:

344

AN:

41552

American (AMR)

AF:

0.0254

AC:

389

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00745

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0310

AC:

329

AN:

10602

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0416

AC:

2832

AN:

68012

Other (OTH)

AF:

0.0289

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

217

434

651

868

1085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0370

Hom.:

419

Bravo

AF:

0.0261

TwinsUK

AF:

0.0407

AC:

151

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.0423

AC:

364

ExAC

AF:

0.0284

AC:

3442

Asia WGS

AF:

0.00491

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.0043

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.3

PhyloP100

2.1

PrimateAI

Benign

0.21

PROVEAN

Benign

1.7

REVEL

Benign

0.034

Sift

Benign

0.68

Sift4G

Benign

0.82

Polyphen

0.0020

Vest4

0.072

MPC

0.069

ClinPred

0.00056

GERP RS

-0.45

Varity_R

0.097

gMVP

0.15

Mutation Taster

=91/9

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over