2-61017754-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002618.4(PEX13):c.-6G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,549,040 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (27 hom.)
• Consequence: PEX13 NM_002618.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.200

Genes affected

PEX13 (HGNC:8855): (peroxisomal biogenesis factor 13) This gene encodes a peroxisomal membrane protein that binds the type 1 peroxisomal targeting signal receptor via a SH3 domain located in the cytoplasm. Mutations and deficiencies in peroxisomal protein importing and peroxisome assembly lead to peroxisomal biogenesis disorders, an example of which is Zellweger syndrome. [provided by RefSeq, Oct 2008]

PUS10 (HGNC:26505): (pseudouridine synthase 10) Pseudouridination, the isomerization of uridine to pseudouridine, is the most common posttranscriptional nucleotide modification found in RNA and is essential for biologic functions such as spliceosome biogenesis. Pseudouridylate synthases, such as PUS10, catalyze pseudouridination of structural RNAs, including transfer, ribosomal, and splicing RNAs. These enzymes also act as RNA chaperones, facilitating the correct folding and assembly of tRNAs (McCleverty et al., 2007 [PubMed 17900615]).[supplied by OMIM, May 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-61017754-G-C is Benign according to our data. Variant chr2-61017754-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 193235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00333 (507/152310) while in subpopulation NFE AF= 0.00513 (349/68016). AF 95% confidence interval is 0.00469. There are 1 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX13	NM_002618.4	c.-6G>C		5_prime_UTR_variant	1/4	ENST00000295030.6
PUS10	NM_144709.4	c.-16+254C>G		intron_variant		ENST00000316752.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX13	ENST00000295030.6	c.-6G>C		5_prime_UTR_variant	1/4	1	NM_002618.4	P1
PUS10	ENST00000316752.11	c.-16+254C>G		intron_variant		1	NM_144709.4	P1

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00337 AC: 510 AN: 151328 Hom.: 2 AF XY: 0.00362 AC XY: 293 AN XY: 80828

Gnomad AFR exome AF: 0.000523

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00932

Gnomad EAS exome AF: 0.0000889

Gnomad SAS exome AF: 0.000885

Gnomad FIN exome AF: 0.00533

Gnomad NFE exome AF: 0.00463

Gnomad OTH exome AF: 0.00348

GnomAD4 exome AF: 0.00498 AC: 6954 AN: 1396730 Hom.: 27 Cov.: 30 AF XY: 0.00490 AC XY: 3372 AN XY: 688786

Gnomad4 AFR exome AF: 0.000697

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00859

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.000961

Gnomad4 FIN exome AF: 0.00387

Gnomad4 NFE exome AF: 0.00567

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74498

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00433 Hom.: 3

Bravo AF: 0.00288

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PEX13: BP4, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 14, 2015

- -

PEX13-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Peroxisome biogenesis disorder 11A (Zellweger) Benign:1

Likely 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 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	-0.77
Cadd	Benign	15
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs147461642; hg19: chr2-61244889;