chr22-18078059-A-G

Position:

• chr22-18078059-A-G

Variant summary

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

The NM_001127649.3(PEX26):​c.-318A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 533,968 control chromosomes in the GnomAD database, including 3,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (907 hom., cov: 32)
  • Exomes 𝑓: 0.10 (2455 hom.)
• Consequence: PEX26 NM_001127649.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.21

Genes affected

PEX26 (HGNC:22965): (peroxisomal biogenesis factor 26) This gene belongs to the peroxin-26 gene family. It is probably required for protein import into peroxisomes. It anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Defects in this gene are the cause of peroxisome biogenesis disorder complementation group 8 (PBD-CG8). PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2010]

ENSG00000288683 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-18078059-A-G is Benign according to our data. Variant chr22-18078059-A-G is described in ClinVar as [Benign]. Clinvar id is 340749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.-318A>G		5_prime_UTR_variant	1/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.-82+12A>G		intron_variant			NP_060399.1
PEX26	NM_001199319.2	c.-82+12A>G		intron_variant			NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744	c.-318A>G		5_prime_UTR_variant	1/5	1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6	n.-82+12A>G		intron_variant		5		ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 14995 AN: 152044 Hom.: 907 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.103 AC: 39312 AN: 381806 Hom.: 2455 Cov.: 0 AF XY: 0.0997 AC XY: 21163 AN XY: 212276

Gnomad4 AFR exome AF: 0.0467

Gnomad4 AMR exome AF: 0.0682

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.000359

Gnomad4 SAS exome AF: 0.0501

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.0985 AC: 14994 AN: 152162 Hom.: 907 Cov.: 32 AF XY: 0.0979 AC XY: 7281 AN XY: 74382

Gnomad4 AFR AF: 0.0476

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.0432

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.110

Alfa AF: 0.113 Hom.: 208

Bravo AF: 0.0954

Asia WGS AF: 0.0240 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2018	- -

Peroxisome biogenesis disorder 7A (Zellweger) 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	-0.85
CADD	Benign	0.20
DANN	Benign	0.33
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: rs62239019; hg19: chr22-18560825;