NM_025009.5:c.142C>T

Variant names:

• chr4-55953113-C-T
• rs202084972
• NM_025009.5:c.142C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_025009.5(CEP135):​c.142C>T​(p.Arg48Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,593,488 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (3 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.07
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36521778).
• BP6: Variant 4-55953113-C-T is Benign according to our data. Variant chr4-55953113-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434720.
• BS2: High Homozygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	NM_025009.5	MANE Select	c.142C>T	p.Arg48Trp	missense	Exon 3 of 26	NP_079285.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	ENST00000257287.5	TSL:1 MANE Select	c.142C>T	p.Arg48Trp	missense	Exon 3 of 26	ENSP00000257287.3	Q66GS9-1
	CEP135	ENST00000916105.1		c.142C>T	p.Arg48Trp	missense	Exon 3 of 27	ENSP00000586164.1
	CEP135	ENST00000916104.1		c.142C>T	p.Arg48Trp	missense	Exon 3 of 26	ENSP00000586163.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000350 AC: 81 AN: 231390 AF XY: 0.000383

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.000172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000315

Gnomad OTH exome AF: 0.000358

GnomAD4 exome AF: 0.000470 AC: 678 AN: 1441372 Hom.: 3 Cov.: 30 AF XY: 0.000523 AC XY: 375 AN XY: 716486

African (AFR) AF: 0.0000937 AC: 3 AN: 32022

American (AMR) AF: 0.000330 AC: 13 AN: 39356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 39004

South Asian (SAS) AF: 0.00135 AC: 110 AN: 81748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.000480 AC: 531 AN: 1105708

Other (OTH) AF: 0.000353 AC: 21 AN: 59508

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152116 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68014

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000471 Hom.: 0

Bravo AF: 0.000295

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.68
MPC		0.37
ClinPred		0.22	T
GERP RS		4.6
Varity_R		0.43
gMVP		0.55
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs202084972; hg19: chr4-56819279; COSMIC: COSV104566291; COSMIC: COSV104566291;