22-18085172-C-A

Position:

• chr22-18085172-C-A

Variant summary

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

The NM_001127649.3(PEX26):​c.728C>A​(p.Ala243Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A243V) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506

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.728C>A	p.Ala243Glu	missense_variant	4/5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.728C>A	p.Ala243Glu	missense_variant	5/6		NP_060399.1
PEX26	NM_001199319.2	c.667+1440C>A		intron_variant			NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744.8	c.728C>A	p.Ala243Glu	missense_variant	4/5	1	NM_001127649.3	ENSP00000382648.4
PEX26	ENST00000329627.11	c.728C>A	p.Ala243Glu	missense_variant	5/6	1		ENSP00000331106.5
PEX26	ENST00000428061.2	c.667+1440C>A		intron_variant		1		ENSP00000412441.2
ENSG00000288683	ENST00000474897.6	n.728C>A		non_coding_transcript_exon_variant	5/9	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.069	T;T
Sift4G	Uncertain	0.042	D;D
Polyphen		0.85	P;P
Vest4		0.51
MutPred		0.53		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.89
MPC		0.58
ClinPred		0.43	T
GERP RS		-2.0
Varity_R		0.084
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs149153003; hg19: chr22-18567938;