rs76659072

chr4-56020725-T-Achr4-56020725-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025009.5(CEP135):c.3265T>A(p.Leu1089Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,613,780 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075767636).
• BP6: Variant 4-56020725-T-A is Benign according to our data. Variant chr4-56020725-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210681.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0023 (351/152320) while in subpopulation AFR AF= 0.00818 (340/41574). AF 95% confidence interval is 0.00746. There are 3 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5	c.3265T>A	p.Leu1089Ile	missense_variant	24/26	ENST00000257287.5
CEP135	XM_006714055.4	c.3232T>A	p.Leu1078Ile	missense_variant	24/26
CEP135	XM_005265788.5	c.2194T>A	p.Leu732Ile	missense_variant	17/19
CEP135	XM_011534412.2	c.1735T>A	p.Leu579Ile	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5	c.3265T>A	p.Leu1089Ile	missense_variant	24/26	1	NM_025009.5	P1
CEP135	ENST00000506202.1	n.3215T>A		non_coding_transcript_exon_variant	17/19	1
CEP135	ENST00000706801.1	n.1330T>A		non_coding_transcript_exon_variant	8/10

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152202 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000533 AC: 134 AN: 251178 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135732

Gnomad AFR exome AF: 0.00750

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000231 AC: 337 AN: 1461460 Hom.: 2 Cov.: 30 AF XY: 0.000204 AC XY: 148 AN XY: 727032

Gnomad4 AFR exome AF: 0.00846

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74474

Gnomad4 AFR AF: 0.00818

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.00214

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 13, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -

CEP135-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2019

This variant is classified as likely 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.063
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.094
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.054	T
Polyphen		0.94	P
Vest4		0.40
MVP		0.32
MPC		0.19
ClinPred		0.046	T
GERP RS		0.65
Varity_R		0.084
gMVP		0.28

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: rs76659072; hg19: chr4-56886891;