13-24882621-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018451.5(CENPJ):c.*556A>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 0.00154 in 154,240 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: CENPJ NM_018451.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.989

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-24882621-T-G is Benign according to our data. Variant chr13-24882621-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 881105.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00153 (233/152318) while in subpopulation SAS AF= 0.00953 (46/4828). AF 95% confidence interval is 0.00734. There are 3 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.*556A>C		3_prime_UTR_variant	17/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.*556A>C		3_prime_UTR_variant	17/17	1	NM_018451.5	P1
CENPJ	ENST00000616936.4	c.*1227A>C		3_prime_UTR_variant, NMD_transcript_variant	16/16	1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152200 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.00260 AC: 5 AN: 1922 Hom.: 0 Cov.: 0 AF XY: 0.00418 AC XY: 4 AN XY: 958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000754

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152318 Hom.: 3 Cov.: 31 AF XY: 0.00168 AC XY: 125 AN XY: 74478

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00953

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00113

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly 6, primary, autosomal recessive Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Seckel syndrome 4 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.76
Dann	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs188324716; hg19: chr13-25456759;