chr4-55953268-C-T

Position:

• chr4-55953268-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_025009.5(CEP135):​c.297C>T​(p.His99=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000865 in 1,508,172 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (4 hom.)
• Consequence: CEP135 NM_025009.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.23

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]

LOC124900705 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-55953268-C-T is Benign according to our data. Variant chr4-55953268-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-55953268-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00294 (448/152170) while in subpopulation AFR AF= 0.00913 (379/41532). AF 95% confidence interval is 0.00837. There are 1 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP135	NM_025009.5	c.297C>T	p.His99=	synonymous_variant	3/26	ENST00000257287.5	NP_079285.2
LOC124900705	XR_007058124.1	n.198-797G>A		intron_variant, non_coding_transcript_variant
CEP135	XM_006714055.4	c.297C>T	p.His99=	synonymous_variant	3/26		XP_006714118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.297C>T	p.His99=	synonymous_variant	3/26	1	NM_025009.5	ENSP00000257287	P1
CEP135	ENST00000422247.6	c.297C>T	p.His99=	synonymous_variant	3/6	2		ENSP00000412799
CEP135	ENST00000706800.1	n.470C>T		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 152052 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00115 AC: 207 AN: 180528 Hom.: 0 AF XY: 0.000946 AC XY: 94 AN XY: 99418

Gnomad AFR exome AF: 0.00971

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.000168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000397

Gnomad OTH exome AF: 0.00337

GnomAD4 exome AF: 0.000631 AC: 856 AN: 1356002 Hom.: 4 Cov.: 26 AF XY: 0.000608 AC XY: 407 AN XY: 668926

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.000410

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000418

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.000361

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152170 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74396

Gnomad4 AFR AF: 0.00913

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00144 Hom.: 2

Bravo AF: 0.00369

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CEP135: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 03, 2013

- -

CEP135-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2021

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
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.62
DANN	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs115408010; hg19: chr4-56819434;