chr4-55953202-A-C

Position:

• chr4-55953202-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025009.5(CEP135):​c.231A>C​(p.Arg77Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.254

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]

LOC124900705 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4223963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP135	NM_025009.5	c.231A>C	p.Arg77Ser	missense_variant	3/26	ENST00000257287.5	NP_079285.2
LOC124900705	XR_007058124.1	n.198-731T>G		intron_variant, non_coding_transcript_variant
CEP135	XM_006714055.4	c.231A>C	p.Arg77Ser	missense_variant	3/26		XP_006714118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.231A>C	p.Arg77Ser	missense_variant	3/26	1	NM_025009.5	ENSP00000257287	P1
CEP135	ENST00000422247.6	c.231A>C	p.Arg77Ser	missense_variant	3/6	2		ENSP00000412799
CEP135	ENST00000706800.1	n.404A>C		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 8, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 13, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.000032	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.84	P;P
Vest4		0.56
MutPred		0.20		Gain of phosphorylation at R77 (P = 0.0422);Gain of phosphorylation at R77 (P = 0.0422);
MVP		0.66
MPC		0.19
ClinPred		0.96	D
GERP RS		2.9
Varity_R		0.25
gMVP		0.46

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: rs1728412496; hg19: chr4-56819368;