rs3742163

chr13-24885398-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018451.5(CENPJ):c.3367-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,575,374 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (238 hom.)
• Consequence: CENPJ NM_018451.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001613
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.06

Genes affected

CENPJ (HGNC:17272): (centromere protein J) This gene encodes a protein that belongs to the centromere protein family. During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway, and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein. Mutations in this gene are associated with primary autosomal recessive microcephaly, a disorder characterized by severely reduced brain size and cognitive disability. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2012]

RNF17 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-24885398-A-G is Benign according to our data. Variant chr13-24885398-A-G is described in ClinVar as [Benign]. Clinvar id is 158209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24885398-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.3367-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.3367-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018451.5	P1

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 808 AN: 152148 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0808

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0115 AC: 2884 AN: 251446 Hom.: 88 AF XY: 0.0100 AC XY: 1359 AN XY: 135894

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0866

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00457

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.00700

GnomAD4 exome AF: 0.00468 AC: 6654 AN: 1423108 Hom.: 238 Cov.: 25 AF XY: 0.00447 AC XY: 3175 AN XY: 710642

Gnomad4 AFR exome AF: 0.000733

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.000618

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.00530

Gnomad4 NFE exome AF: 0.000452

Gnomad4 OTH exome AF: 0.00568

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152266 Hom.: 22 Cov.: 33 AF XY: 0.00607 AC XY: 452 AN XY: 74470

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0808

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00708

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Seckel syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Microcephaly 6, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	9.9
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.17		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: rs3742163; hg19: chr13-25459536; COSMIC: COSV67883514; COSMIC: COSV67883514;