4-55954246-G-A

Position:

• chr4-55954246-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.335G>A​(p.Arg112His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,600,192 control chromosomes in the GnomAD database, including 1,177 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (69 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1108 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08

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]

CEP135 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016501546).
• BP6: Variant 4-55954246-G-A is Benign according to our data. Variant chr4-55954246-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-55954246-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.027 (4115/152276) while in subpopulation NFE AF= 0.0416 (2832/68012). AF 95% confidence interval is 0.0404. There are 69 homozygotes in gnomad4. There are 1919 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP135	NM_025009.5	c.335G>A	p.Arg112His	missense_variant	4/26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.335G>A	p.Arg112His	missense_variant	4/26		XP_006714118.1
LOC124900705	XR_007058124.1	n.198-1775C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.335G>A	p.Arg112His	missense_variant	4/26	1	NM_025009.5	ENSP00000257287.3
CEP135	ENST00000422247.6	c.335G>A	p.Arg112His	missense_variant	4/6	2		ENSP00000412799.2
CEP135	ENST00000706800.1	n.508G>A		non_coding_transcript_exon_variant	4/5
CEP135	ENST00000515081.1	n.-32G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4117 AN: 152158 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0285 AC: 6877 AN: 241070 Hom.: 129 AF XY: 0.0294 AC XY: 3838 AN XY: 130456

Gnomad AFR exome AF: 0.00696

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00964

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.0436

Gnomad OTH exome AF: 0.0321

GnomAD4 exome AF: 0.0362 AC: 52408 AN: 1447916 Hom.: 1108 Cov.: 30 AF XY: 0.0357 AC XY: 25695 AN XY: 719994

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0291

Gnomad4 EAS exome AF: 0.0000769

Gnomad4 SAS exome AF: 0.00946

Gnomad4 FIN exome AF: 0.0324

Gnomad4 NFE exome AF: 0.0416

Gnomad4 OTH exome AF: 0.0336

GnomAD4 genome AF: 0.0270 AC: 4115 AN: 152276 Hom.: 69 Cov.: 33 AF XY: 0.0258 AC XY: 1919 AN XY: 74448

Gnomad4 AFR AF: 0.00828

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0382 Hom.: 228

Bravo AF: 0.0261

TwinsUK AF: 0.0407 AC: 151

ALSPAC AF: 0.0355 AC: 137

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0423 AC: 364

ExAC AF: 0.0284 AC: 3442

Asia WGS AF: 0.00491 AC: 17 AN: 3474

ClinVar

Significance: Benign/Likely 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.37
DEOGEN2	Benign	0.0043	.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.3	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.7	N;N
REVEL	Benign	0.034
Sift	Benign	0.68	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0020	B;B
Vest4		0.072
MPC		0.069
ClinPred		0.00056	T
GERP RS		-0.45
Varity_R		0.097
gMVP		0.15

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: rs77591659; hg19: chr4-56820412;