4-55974750-A-G

Position:

• chr4-55974750-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_025009.5(CEP135):​c.1254A>G​(p.Arg418=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,610,356 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 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: CEP135 NM_025009.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.17

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 Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 4-55974750-A-G is Benign according to our data. Variant chr4-55974750-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-55974750-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00255 (388/152310) while in subpopulation AFR AF= 0.00881 (366/41562). AF 95% confidence interval is 0.00806. There are 0 homozygotes in gnomad4. There are 181 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.1254A>G	p.Arg418=	synonymous_variant	11/26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4	c.1221A>G	p.Arg407=	synonymous_variant	11/26		XP_006714118.1
CEP135	XM_005265788.5	c.183A>G	p.Arg61=	synonymous_variant	4/19		XP_005265845.1
CEP135	XM_011534412.2	c.-58+3342A>G		intron_variant			XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5	c.1254A>G	p.Arg418=	synonymous_variant	11/26	1	NM_025009.5	ENSP00000257287	P1
CEP135	ENST00000506202.1	n.1204A>G		non_coding_transcript_exon_variant	4/19	1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00883

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.000785 AC: 195 AN: 248494 Hom.: 0 AF XY: 0.000604 AC XY: 81 AN XY: 134204

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1458046 Hom.: 1 Cov.: 30 AF XY: 0.000215 AC XY: 156 AN XY: 725126

Gnomad4 AFR exome AF: 0.00947

Gnomad4 AMR exome AF: 0.000476

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000432

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74460

Gnomad4 AFR AF: 0.00881

Gnomad4 AMR AF: 0.000719

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: 0.00135 Hom.: 0

Bravo AF: 0.00301

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	CEP135: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.9
DANN	Benign	0.66

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: rs62641662; hg19: chr4-56840916;