rs74315506

Variant names:

• chr22-18078378-T-C
• rs74315506
• NM_001127649.3:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-18078378-T-C
• chr22-18078378-T-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001127649.3(PEX26):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PEX26 NM_001127649.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.58
• Publications: 7 publications found

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]

PEX26 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 7A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• peroxisome biogenesis disorder 7B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288683 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 22 pathogenic variants. Next in-frame start position is after 96 codons. Genomic position: 18079929. Lost 0.312 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-18078378-T-C is Pathogenic according to our data. Variant chr22-18078378-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.2T>C	p.Met1?	start_lost	Exon 2 of 6		NP_060399.1
PEX26	NM_001199319.2	c.2T>C	p.Met1?	start_lost	Exon 2 of 5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6	n.2T>C		non_coding_transcript_exon_variant	Exon 2 of 9	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447764 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719838

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.00 AC: 0 AN: 84716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106034

Other (OTH) AF: 0.00 AC: 0 AN: 59938

GnomAD4 genome Cov.: 32

Alfa AF: 0.000529 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:2

Sep 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PEX26 mRNA. The next in-frame methionine is located at codon 96. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with PEX26-related conditions (PMID: 12851857). ClinVar contains an entry for this variant (Variation ID: 2156). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects PEX26 function (PMID: 12851857). This variant disrupts a region of the PEX26 protein in which other variant(s) (p.Gly89Arg) have been determined to be pathogenic (PMID: 12851857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1

Aug 17, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PEX26 c.2T>C (p.Met1?) variant is predicted to disrupt the initiator codon and thus may interfere with protein expression. This variant has been reported in two individuals with infantile Refsum disease, both of whom were compound heterozygous for this variant and the same missense variant (Matsumoto et al. 2003; Weller et al. 2005). Another variant (c.3T>C) that results in the same protein consequence has been reported in a compound heterozygous state in an individual with hearing loss and enamel defects, consistent with Heimler syndrome (Neuhaus et al. 2017). The p.Met1? variant was absent from 106 control chromosomes but is reported at a frequency of 0.000062 in the East Asian population of the Genome Aggregation Database. However, this frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Studies in patient and non-patient cells have demonstrated that the variant impairs protein function, including less effective recruitment of Pex1p-Pex6p complexes to peroxisomes and reduced peroxisomal protein import (Matsumoto et al. 2003; Weller et al. 2005; Furuki et al. 2006). Due to the potential impact of initiator codon variants and the available literature, the p.Met1? variant is classified as likely pathogenic for Zellweger syndrome spectrum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:1

Feb 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12851857, 15858711, 16257970) -

Peroxisome biogenesis disorder 7B Pathogenic:1

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D;.;D;.
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		1.6
PROVEAN	Uncertain	-2.7	.;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.83
MutPred		0.83		Loss of stability (P = 0.0017);Loss of stability (P = 0.0017);Loss of stability (P = 0.0017);Loss of stability (P = 0.0017);
MVP		0.99
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.63
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74315506; hg19: chr22-18561144;