chr13-24882773-G-A

Position:

• chr13-24882773-G-A

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.*404C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 189,004 control chromosomes in the GnomAD database, including 1,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1558 hom., cov: 32)
  • Exomes 𝑓: 0.12 (326 hom.)
• Consequence: CENPJ NM_018451.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.47

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=-0.91).
• BP6: Variant 13-24882773-G-A is Benign according to our data. Variant chr13-24882773-G-A is described in ClinVar as [Benign]. Clinvar id is 311597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.*404C>T		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.*404C>T		3_prime_UTR_variant	17/17	1	NM_018451.5	ENSP00000371308	P1
CENPJ	ENST00000616936.4	c.*1075C>T		3_prime_UTR_variant, NMD_transcript_variant	16/16	1		ENSP00000477511

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20537 AN: 151864 Hom.: 1555 Cov.: 32

Gnomad AFR AF: 0.0987

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.0929

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.134

GnomAD4 exome AF: 0.116 AC: 4293 AN: 37022 Hom.: 326 Cov.: 0 AF XY: 0.111 AC XY: 2135 AN XY: 19270

Gnomad4 AFR exome AF: 0.0601

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.0419

Gnomad4 EAS exome AF: 0.253

Gnomad4 SAS exome AF: 0.0673

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.135 AC: 20548 AN: 151982 Hom.: 1558 Cov.: 32 AF XY: 0.136 AC XY: 10120 AN XY: 74282

Gnomad4 AFR AF: 0.0987

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.0936

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.133

Alfa AF: 0.129 Hom.: 292

Bravo AF: 0.135

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 12, 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 12, 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	-0.91
CADD	Benign	0.30
DANN	Benign	0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs77868928; hg19: chr13-25456911;