22-18088085-C-T

Position:

• chr22-18088085-C-T

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.*10C>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 0.00925 in 1,547,536 control chromosomes in the GnomAD database, including 1,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (144 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (1097 hom.)
• Consequence: PEX26 NM_001127649.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: -2.47

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=-0.9).
• BP6: Variant 22-18088085-C-T is Benign according to our data. Variant chr22-18088085-C-T is described in ClinVar as [Benign]. Clinvar id is 167457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.*10C>T		3_prime_UTR_variant	5/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.*10C>T		3_prime_UTR_variant	6/6		NP_060399.1
PEX26	NM_001199319.2	c.*10C>T		3_prime_UTR_variant	5/5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.*10C>T		3_prime_UTR_variant	5/5	1	NM_001127649.3	ENSP00000382648.4
PEX26	ENST00000329627.11	c.*10C>T		3_prime_UTR_variant	6/6	1		ENSP00000331106.5
PEX26	ENST00000428061.2	c.*10C>T		3_prime_UTR_variant	4/4	1		ENSP00000412441.2
ENSG00000288683	ENST00000474897.6	n.814+2827C>T		intron_variant		5		ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2065 AN: 152182 Hom.: 139 Cov.: 33

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0989

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0593

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0349 AC: 8722 AN: 249604 Hom.: 939 AF XY: 0.0271 AC XY: 3654 AN XY: 135024

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0635

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.00877 AC: 12237 AN: 1395236 Hom.: 1097 Cov.: 25 AF XY: 0.00764 AC XY: 5329 AN XY: 697856

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.0553

Gnomad4 SAS exome AF: 0.00460

Gnomad4 FIN exome AF: 0.0000978

Gnomad4 NFE exome AF: 0.000345

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0137 AC: 2085 AN: 152300 Hom.: 144 Cov.: 33 AF XY: 0.0150 AC XY: 1120 AN XY: 74492

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.0997

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0596

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00164 Hom.: 5

Bravo AF: 0.0229

Asia WGS AF: 0.0440 AC: 153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2017	Variant summary: The PEX26 c.*10C>T variant involves the alteration of a non-conserved nucleotide located in the 3' UTR. One in silico tool predicts a benign outcome for this variant. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 3291/121166 (358 homozygotes, 1/36), which is approximately 17 times the estimated maximal expected allele frequency of a pathogenic PEX26 variant of 1/632, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories have cited the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2014	- -

Peroxisome biogenesis disorder 7A (Zellweger) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117472525; hg19: chr22-18570851;