4-55954246-G-A

Variant names:

• chr4-55954246-G-A
• rs77591659
• NM_025009.5:c.335G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112C) has been classified as Uncertain significance.

• 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
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 8, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124900705 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 128703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025009.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	NM_025009.5	MANE Select	c.335G>A	p.Arg112His	missense	Exon 4 of 26	NP_079285.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	ENST00000257287.5	TSL:1 MANE Select	c.335G>A	p.Arg112His	missense	Exon 4 of 26	ENSP00000257287.3
	CEP135	ENST00000422247.6	TSL:2	c.335G>A	p.Arg112His	missense	Exon 4 of 6	ENSP00000412799.2
	CEP135	ENST00000706800.1		n.508G>A		non_coding_transcript_exon	Exon 4 of 5

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

GnomAD2 exomes AF: 0.0285 AC: 6877 AN: 241070 AF XY: 0.0294

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 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

African (AFR) AF: 0.00621 AC: 204 AN: 32848

American (AMR) AF: 0.0169 AC: 717 AN: 42320

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 751 AN: 25820

East Asian (EAS) AF: 0.0000769 AC: 3 AN: 39008

South Asian (SAS) AF: 0.00946 AC: 787 AN: 83222

European-Finnish (FIN) AF: 0.0324 AC: 1724 AN: 53178

Middle Eastern (MID) AF: 0.0363 AC: 207 AN: 5700

European-Non Finnish (NFE) AF: 0.0416 AC: 46009 AN: 1106078

Other (OTH) AF: 0.0336 AC: 2006 AN: 59742

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

African (AFR) AF: 0.00828 AC: 344 AN: 41552

American (AMR) AF: 0.0254 AC: 389 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.0310 AC: 329 AN: 10602

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2832 AN: 68012

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0370 Hom.: 419

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 01, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.3	N
PhyloP100		2.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.034
Sift	Benign	0.68	T
Sift4G	Benign	0.82	T
Polyphen		0.0020	B
Vest4		0.072
MPC		0.069
ClinPred		0.00056	T
GERP RS		-0.45
Varity_R		0.097
gMVP		0.15
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77591659; hg19: chr4-56820412;