rs139407231

Positions:

• chr4-55999357-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_025009.5(CEP135):​c.2065A>G​(p.Ile689Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,614,210 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.882

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0049135685).
• BP6: Variant 4-55999357-A-G is Benign according to our data. Variant chr4-55999357-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 434722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00232 (353/152376) while in subpopulation AFR AF= 0.00774 (322/41592). AF 95% confidence interval is 0.00705. There are 1 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5	c.2065A>G	p.Ile689Val	missense_variant	16/26	ENST00000257287.5
CEP135	XM_006714055.4	c.2032A>G	p.Ile678Val	missense_variant	16/26
CEP135	XM_005265788.5	c.994A>G	p.Ile332Val	missense_variant	9/19
CEP135	XM_011534412.2	c.535A>G	p.Ile179Val	missense_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5	c.2065A>G	p.Ile689Val	missense_variant	16/26	1	NM_025009.5	P1
CEP135	ENST00000506202.1	n.2015A>G		non_coding_transcript_exon_variant	9/19	1
CEP135	ENST00000706801.1	n.57A>G		non_coding_transcript_exon_variant	1/10

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152258 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.00239

GnomAD3 exomes AF: 0.000661 AC: 166 AN: 251252 Hom.: 1 AF XY: 0.000471 AC XY: 64 AN XY: 135828

Gnomad AFR exome AF: 0.00920

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000225 AC: 329 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.000183 AC XY: 133 AN XY: 727218

Gnomad4 AFR exome AF: 0.00800

Gnomad4 AMR exome AF: 0.000559

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: 0.000480

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152376 Hom.: 1 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74512

Gnomad4 AFR AF: 0.00774

Gnomad4 AMR AF: 0.00157

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: 0.00236

Alfa AF: 0.000372 Hom.: 0

Bravo AF: 0.00242

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	CEP135: BP4 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 15, 2016

- -

CEP135-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as 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	0.056
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.018
DANN	Benign	0.22
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.085
Sift	Benign	0.86	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.082
MVP		0.14
MPC		0.051
ClinPred		0.0043	T
GERP RS		-5.5
Varity_R		0.020
gMVP		0.037

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139407231; hg19: chr4-56865523;