4-56020725-T-G

Variant names:

• chr4-56020725-T-G
• rs76659072
• NM_025009.5:c.3265T>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.3265T>G​(p.Leu1089Val) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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=0.18127576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP135	NM_025009.5	c.3265T>G	p.Leu1089Val	missense_variant	Exon 24 of 26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.3232T>G	p.Leu1078Val	missense_variant	Exon 24 of 26		XP_006714118.1
CEP135	XM_005265788.5	c.2194T>G	p.Leu732Val	missense_variant	Exon 17 of 19		XP_005265845.1
CEP135	XM_011534412.2	c.1735T>G	p.Leu579Val	missense_variant	Exon 14 of 16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.3265T>G	p.Leu1089Val	missense_variant	Exon 24 of 26	1	NM_025009.5	ENSP00000257287.3
CEP135	ENST00000506202.1	n.3215T>G		non_coding_transcript_exon_variant	Exon 17 of 19	1
CEP135	ENST00000706801.1	n.1330T>G		non_coding_transcript_exon_variant	Exon 8 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251178 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.019
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.10
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.033	D
Polyphen		0.94	P
Vest4		0.24
MutPred		0.19		Gain of methylation at K1085 (P = 0.0902);
MVP		0.35
MPC		0.15
ClinPred		0.62	D
GERP RS		0.65
Varity_R		0.094
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs76659072; hg19: chr4-56886891;