rs145959811

chr4-56011950-G-A

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.2767G>A(p.Glu923Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00189 in 1,576,822 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.08

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=0.01546675).
• BP6: Variant 4-56011950-G-A is Benign according to our data. Variant chr4-56011950-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210679.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00156 (237/152282) while in subpopulation NFE AF= 0.00293 (199/68028). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5	c.2767G>A	p.Glu923Lys	missense_variant	21/26	ENST00000257287.5
CEP135	XM_006714055.4	c.2734G>A	p.Glu912Lys	missense_variant	21/26
CEP135	XM_005265788.5	c.1696G>A	p.Glu566Lys	missense_variant	14/19
CEP135	XM_011534412.2	c.1237G>A	p.Glu413Lys	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5	c.2767G>A	p.Glu923Lys	missense_variant	21/26	1	NM_025009.5	P1
CEP135	ENST00000506202.1	n.2717G>A		non_coding_transcript_exon_variant	14/19	1
CEP135	ENST00000706801.1	n.832G>A		non_coding_transcript_exon_variant	5/10

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00147 AC: 325 AN: 221644 Hom.: 2 AF XY: 0.00156 AC XY: 188 AN XY: 120464

Gnomad AFR exome AF: 0.000274

Gnomad AMR exome AF: 0.000593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000318

Gnomad FIN exome AF: 0.00155

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.00193 AC: 2746 AN: 1424540 Hom.: 2 Cov.: 31 AF XY: 0.00195 AC XY: 1383 AN XY: 708092

Gnomad4 AFR exome AF: 0.000287

Gnomad4 AMR exome AF: 0.000688

Gnomad4 ASJ exome AF: 0.000161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000390

Gnomad4 FIN exome AF: 0.00171

Gnomad4 NFE exome AF: 0.00226

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74466

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00210 Hom.: 1

Bravo AF: 0.00149

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 04, 2014

- -

CEP135-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2022

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.26
MVP		0.75
MPC		0.38
ClinPred		0.046	T
GERP RS		5.7
Varity_R		0.69
gMVP		0.32

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: rs145959811; hg19: chr4-56878116;