rs150578085

Positions:

• chr4-55974908-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_025009.5(CEP135):​c.1412G>A​(p.Arg471Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,613,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.67

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0256176).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000447 (68/152270) while in subpopulation AMR AF= 0.000916 (14/15292). AF 95% confidence interval is 0.000553. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP135	NM_025009.5	c.1412G>A	p.Arg471Lys	missense_variant	11/26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.1379G>A	p.Arg460Lys	missense_variant	11/26		XP_006714118.1
CEP135	XM_005265788.5	c.341G>A	p.Arg114Lys	missense_variant	4/19		XP_005265845.1
CEP135	XM_011534412.2	c.-58+3500G>A		intron_variant			XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.1412G>A	p.Arg471Lys	missense_variant	11/26	1	NM_025009.5	ENSP00000257287	P1
CEP135	ENST00000506202.1	n.1362G>A		non_coding_transcript_exon_variant	4/19	1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000446 AC: 112 AN: 250910 Hom.: 0 AF XY: 0.000553 AC XY: 75 AN XY: 135596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000784

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000651 AC: 951 AN: 1460838 Hom.: 0 Cov.: 31 AF XY: 0.000633 AC XY: 460 AN XY: 726612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.000789

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74452

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000669

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000219

EpiControl AF: 0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2022	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 471 of the CEP135 protein (p.Arg471Lys). This variant is present in population databases (rs150578085, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. 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: 210674). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.049
Sift	Benign	0.19	T
Sift4G	Benign	0.81	T
Polyphen		0.029	B
Vest4		0.23
MVP		0.41
MPC		0.059
ClinPred		0.025	T
GERP RS		4.2
Varity_R		0.092
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: rs150578085; hg19: chr4-56841074;