chr22-18078393-C-T

Position:

• chr22-18078393-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127649.3(PEX26):​c.17C>T​(p.Ser6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,447,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.17C>T	p.Ser6Leu	missense_variant	1/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.17C>T	p.Ser6Leu	missense_variant	2/6		NP_060399.1
PEX26	NM_001199319.2	c.17C>T	p.Ser6Leu	missense_variant	2/5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.17C>T	p.Ser6Leu	missense_variant	1/5	1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6	n.17C>T		non_coding_transcript_exon_variant	2/9	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000462 AC: 1 AN: 216496 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 119554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447912 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 719668

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PEX26-related conditions. This sequence change replaces serine with leucine at codon 6 of the PEX26 protein (p.Ser6Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.093	N
LIST_S2	Uncertain	0.88	D;.;D;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.4	M;M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	.;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	.;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.24
MutPred		0.45		Loss of phosphorylation at S6 (P = 0.0089);Loss of phosphorylation at S6 (P = 0.0089);Loss of phosphorylation at S6 (P = 0.0089);Loss of phosphorylation at S6 (P = 0.0089);
MVP		0.98
MPC		0.16
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770013891; hg19: chr22-18561159;