4-55953113-C-T

Position:

chr4-55953113-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_025009.5(CEP135):c.142C>T(p.Arg48Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,593,488 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00047 ( 3 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.07

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 links:

LOC124900705 (HGNC:):

LOC124900705 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36521778).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00047 (678/1441372) while in subpopulation SAS AF= 0.00135 (110/81748). AF 95% confidence interval is 0.00114. There are 3 homozygotes in gnomad4_exome. There are 375 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CEP135	NM_025009.5 linkuse as main transcript	c.142C>T	p.Arg48Trp	missense_variant	3/26	ENST00000257287.5
LOC124900705	XR_007058124.1 linkuse as main transcript	n.198-642G>A		intron_variant, non_coding_transcript_variant
CEP135	XM_006714055.4 linkuse as main transcript	c.142C>T	p.Arg48Trp	missense_variant	3/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5 linkuse as main transcript	c.142C>T	p.Arg48Trp	missense_variant	3/26	1	NM_025009.5	P1	Q66GS9-1
CEP135	ENST00000422247.6 linkuse as main transcript	c.142C>T	p.Arg48Trp	missense_variant	3/6	2			Q66GS9-2
CEP135	ENST00000706800.1 linkuse as main transcript	n.315C>T		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000350

AC:

AN:

231390

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

125256

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.000172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00149

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000315

Gnomad OTH exome

AF:

0.000358

GnomAD4 exome

AF:

0.000470

AC:

678

AN:

1441372

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

375

AN XY:

716486

show subpopulations

Gnomad4 AFR exome

AF:

0.0000937

Gnomad4 AMR exome

AF:

0.000330

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00135

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000480

Gnomad4 OTH exome

AF:

0.000353

GnomAD4 genome

AF:

0.000256

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000459

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 48 of the CEP135 protein (p.Arg48Trp). This variant is present in population databases (rs202084972, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CEP135-related conditions. ClinVar contains an entry for this variant (Variation ID: 434720). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

.;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.81

MVP

0.68

MPC

0.37

ClinPred

0.22

GERP RS

4.6

Varity_R

0.43

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over