rs376309359

chr4-56019496-C-Achr4-56019496-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025009.5(CEP135):c.3156C>A(p.His1052Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H1052H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CEP135 NM_025009.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017094463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5	c.3156C>A	p.His1052Gln	missense_variant	23/26	ENST00000257287.5
CEP135	XM_006714055.4	c.3123C>A	p.His1041Gln	missense_variant	23/26
CEP135	XM_005265788.5	c.2085C>A	p.His695Gln	missense_variant	16/19
CEP135	XM_011534412.2	c.1626C>A	p.His542Gln	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5	c.3156C>A	p.His1052Gln	missense_variant	23/26	1	NM_025009.5	P1
CEP135	ENST00000506202.1	n.3106C>A		non_coding_transcript_exon_variant	16/19	1
CEP135	ENST00000706801.1	n.1221C>A		non_coding_transcript_exon_variant	7/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250760 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.0030
Dann	Benign	0.48
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.078		Loss of glycosylation at S1047 (P = 0.1217);
MVP		0.067
MPC		0.059
ClinPred		0.027	T
GERP RS		-9.9
Varity_R		0.043
gMVP		0.13

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: rs376309359; hg19: chr4-56885662;