chr22-18078378-T-C

Position:

• chr22-18078378-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate 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:3
• Conservation: PhyloP100: 1.58

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001127649.3 (PEX26) was described as [Likely_pathogenic] in Lovd
• 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 [Likely_pathogenic]. Clinvar id is 2156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 17, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2022

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2003

- -

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
MutationTaster	Benign	1.0	A;A;A
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.63

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: rs74315506; hg19: chr22-18561144;