rs150331261

Positions:

• chr4-55959705-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_025009.5(CEP135):​c.638T>C​(p.Val213Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000392 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 6.52

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029255748).
• BP6: Variant 4-55959705-T-C is Benign according to our data. Variant chr4-55959705-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 198263.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 = 0.0022 (335/152278) while in subpopulation AFR AF= 0.00756 (314/41556). AF 95% confidence interval is 0.00687. There are 0 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP135	NM_025009.5	c.638T>C	p.Val213Ala	missense_variant	6/26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.638T>C	p.Val213Ala	missense_variant	6/26		XP_006714118.1
LOC124900705	XR_007058124.1	n.198-7234A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.638T>C	p.Val213Ala	missense_variant	6/26	1	NM_025009.5	ENSP00000257287.3
CEP135	ENST00000422247.6	c.638T>C	p.Val213Ala	missense_variant	6/6	2		ENSP00000412799.2
CEP135	ENST00000515081.1	n.272T>C		non_coding_transcript_exon_variant	3/5	2
CEP135	ENST00000706800.1	n.3128T>C		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000660 AC: 166 AN: 251364 Hom.: 0 AF XY: 0.000501 AC XY: 68 AN XY: 135850

Gnomad AFR exome AF: 0.00861

Gnomad AMR exome AF: 0.000579

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: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000203 AC: 297 AN: 1461780 Hom.: 1 Cov.: 30 AF XY: 0.000165 AC XY: 120 AN XY: 727184

Gnomad4 AFR exome AF: 0.00756

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74462

Gnomad4 AFR AF: 0.00756

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000459 Hom.: 0

Bravo AF: 0.00257

ESP6500AA AF: 0.00976 AC: 43

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000881 AC: 107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 22, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	- -

Microcephaly 8, primary, autosomal recessive Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;T
Polyphen		0.74	P;P
Vest4		0.41
MVP		0.72
MPC		0.37
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.41
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150331261; hg19: chr4-56825871;