chr13-24882538-A-G

Position:

• chr13-24882538-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.*639T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,728 control chromosomes in the GnomAD database, including 1,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1257 hom., cov: 31)
  • Exomes 𝑓: 0.081 (5 hom.)
• Consequence: CENPJ NM_018451.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0170

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=-0.92).
• BP6: Variant 13-24882538-A-G is Benign according to our data. Variant chr13-24882538-A-G is described in ClinVar as [Benign]. Clinvar id is 311589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.*639T>C		3_prime_UTR_variant	17/17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.*639T>C		3_prime_UTR_variant	17/17	1	NM_018451.5	ENSP00000371308	P1
CENPJ	ENST00000616936.4	c.*1310T>C		3_prime_UTR_variant, NMD_transcript_variant	16/16	1		ENSP00000477511

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18839 AN: 152006 Hom.: 1258 Cov.: 31

Gnomad AFR AF: 0.0877

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0895

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.0811 AC: 49 AN: 604 Hom.: 5 Cov.: 0 AF XY: 0.0909 AC XY: 32 AN XY: 352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0781

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.0885

Gnomad4 OTH exome AF: 0.0385

GnomAD4 genome AF: 0.124 AC: 18841 AN: 152124 Hom.: 1257 Cov.: 31 AF XY: 0.121 AC XY: 8974 AN XY: 74370

Gnomad4 AFR AF: 0.0875

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0895

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.129

Alfa AF: 0.144 Hom.: 361

Bravo AF: 0.122

Asia WGS AF: 0.0520 AC: 183 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.30
DANN	Benign	0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61947515; hg19: chr13-25456676;