rs141330867

Variant names:

• chr4-56011440-T-C
• rs141330867
• NM_025009.5:c.2534T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_025009.5(CEP135):​c.2534T>C​(p.Val845Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000608 in 1,612,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.60
• Publications: 7 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025742203).
• BP6: Variant 4-56011440-T-C is Benign according to our data. Variant chr4-56011440-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210678.

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.2534T>C	p.Val845Ala	missense	Exon 20 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.2534T>C	p.Val845Ala	missense	Exon 20 of 26	ENSP00000257287.3
	CEP135	ENST00000506202.1	TSL:1	n.2484T>C		non_coding_transcript_exon	Exon 13 of 19
	CEP135	ENST00000916105.1		c.2534T>C	p.Val845Ala	missense	Exon 20 of 27	ENSP00000586164.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 250014 AF XY: 0.000185

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000961

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000548 AC: 80 AN: 1460228 Hom.: 1 Cov.: 30 AF XY: 0.0000496 AC XY: 36 AN XY: 726254

African (AFR) AF: 0.0000599 AC: 2 AN: 33412

American (AMR) AF: 0.000854 AC: 38 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.000934 AC: 37 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111494

Other (OTH) AF: 0.0000166 AC: 1 AN: 60346

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74448

African (AFR) AF: 0.000144 AC: 6 AN: 41562

American (AMR) AF: 0.000589 AC: 9 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	Microcephaly 8, primary, autosomal recessive (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.083
Sift	Benign	0.16	T
Sift4G	Benign	0.91	T
Polyphen		0.48	P
Vest4		0.26
MVP		0.45
MPC		0.10
ClinPred		0.059	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.19
Mutation Taster		=94/6	polymorphism

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: rs141330867; hg19: chr4-56877606; COSMIC: COSV57260453;