chr4-56020738-A-G

Position:

• chr4-56020738-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025009.5(CEP135):​c.3278A>G​(p.Tyr1093Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.588

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077524334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP135	NM_025009.5	c.3278A>G	p.Tyr1093Cys	missense_variant	24/26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.3245A>G	p.Tyr1082Cys	missense_variant	24/26		XP_006714118.1
CEP135	XM_005265788.5	c.2207A>G	p.Tyr736Cys	missense_variant	17/19		XP_005265845.1
CEP135	XM_011534412.2	c.1748A>G	p.Tyr583Cys	missense_variant	14/16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.3278A>G	p.Tyr1093Cys	missense_variant	24/26	1	NM_025009.5	ENSP00000257287	P1
CEP135	ENST00000506202.1	n.3228A>G		non_coding_transcript_exon_variant	17/19	1
CEP135	ENST00000706801.1	n.1343A>G		non_coding_transcript_exon_variant	8/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461388 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.054
Sift	Uncertain	0.016	D
Sift4G	Benign	0.14	T
Polyphen		0.79	P
Vest4		0.27
MutPred		0.30		Loss of phosphorylation at Y1093 (P = 0.0243);
MVP		0.26
MPC		0.23
ClinPred		0.62	D
GERP RS		0.13
Varity_R		0.094
gMVP		0.38

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: rs1553895735; hg19: chr4-56886904;