rs115701891

Positions:

• chr4-55981275-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025009.5(CEP135):​c.1675G>A​(p.Ala559Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,597,440 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.577

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]

CEP135 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023153126).
• BP6: Variant 4-55981275-G-A is Benign according to our data. Variant chr4-55981275-G-A is described in ClinVar as [Benign]. Clinvar id is 128694.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 = 0.0106 (1605/152090) while in subpopulation AFR AF= 0.0371 (1537/41476). AF 95% confidence interval is 0.0355. There are 29 homozygotes in gnomad4. There are 764 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP135	NM_025009.5	c.1675G>A	p.Ala559Thr	missense_variant	13/26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.1642G>A	p.Ala548Thr	missense_variant	13/26		XP_006714118.1
CEP135	XM_005265788.5	c.604G>A	p.Ala202Thr	missense_variant	6/19		XP_005265845.1
CEP135	XM_011534412.2	c.145G>A	p.Ala49Thr	missense_variant	3/16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.1675G>A	p.Ala559Thr	missense_variant	13/26	1	NM_025009.5	ENSP00000257287.3
CEP135	ENST00000506202.1	n.1625G>A		non_coding_transcript_exon_variant	6/19	1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1605 AN: 151972 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00269 AC: 634 AN: 235322 Hom.: 11 AF XY: 0.00198 AC XY: 252 AN XY: 127456

Gnomad AFR exome AF: 0.0394

Gnomad AMR exome AF: 0.00102

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: 0.0000643

Gnomad OTH exome AF: 0.000894

GnomAD4 exome AF: 0.00102 AC: 1470 AN: 1445350 Hom.: 27 Cov.: 30 AF XY: 0.000892 AC XY: 641 AN XY: 718268

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000181

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.0106 AC: 1605 AN: 152090 Hom.: 29 Cov.: 32 AF XY: 0.0103 AC XY: 764 AN XY: 74336

Gnomad4 AFR AF: 0.0371

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00195 Hom.: 4

Bravo AF: 0.0119

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00360 AC: 437

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.5
DANN	Benign	0.16
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.013
Sift	Benign	0.69	T
Sift4G	Benign	0.33	T
Polyphen		0.16	B
Vest4		0.065
MVP		0.20
MPC		0.057
ClinPred		0.0034	T
GERP RS		0.56
Varity_R		0.028
gMVP		0.051

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: rs115701891; hg19: chr4-56847441;