22-18077981-C-T

Position:

• chr22-18077981-C-T

Variant summary

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

The ENST00000329627(PEX26):​c.-148C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00652 in 414,348 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (12 hom.)
• Consequence: PEX26 ENST00000329627 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.51

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]

ENSG00000225335 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-18077981-C-T is Benign according to our data. Variant chr22-18077981-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 340745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0147 (2234/152234) while in subpopulation AFR AF= 0.0499 (2074/41524). AF 95% confidence interval is 0.0482. There are 63 homozygotes in gnomad4. There are 1079 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.18077981C>T		intergenic_region
PEX26	NM_001127649.3	c.-396C>T		upstream_gene_variant		ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.-148C>T		upstream_gene_variant			NP_060399.1
PEX26	NM_001199319.2	c.-148C>T		upstream_gene_variant			NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.-396C>T		upstream_gene_variant		1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6	n.-148C>T		upstream_gene_variant		5		ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2230 AN: 152122 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00179 AC: 468 AN: 262114 Hom.: 12 Cov.: 0 AF XY: 0.00138 AC XY: 206 AN XY: 149324

Gnomad4 AFR exome AF: 0.0528

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000389

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000620

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.0147 AC: 2234 AN: 152234 Hom.: 63 Cov.: 32 AF XY: 0.0145 AC XY: 1079 AN XY: 74424

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00781 Hom.: 3

Bravo AF: 0.0166

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.86
CADD	Benign	0.42
DANN	Benign	0.89

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: rs115617644; hg19: chr22-18560747;