rs544836312

Variant names:

• chr22-18077926-G-A
• rs544836312
• ENST00000329627.11:c.-203G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-18077926-G-A
• chr22-18077926-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000329627.11(PEX26):​c.-203G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 361,352 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: PEX26 ENST00000329627.11 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.708
• Publications: 0 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

ENSG00000225335 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00067 (102/152290) while in subpopulation SAS AF = 0.0205 (99/4822). AF 95% confidence interval is 0.0173. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000329627.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	NM_001127649.3	MANE Select	c.-451G>A		upstream_gene	N/A	NP_001121121.1	Q7Z412-1
	PEX26	NM_017929.6		c.-203G>A		upstream_gene	N/A	NP_060399.1	Q7Z412-1
	PEX26	NM_001199319.2		c.-203G>A		upstream_gene	N/A	NP_001186248.1	Q7Z412-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	ENST00000329627.11	TSL:1	c.-203G>A		5_prime_UTR	Exon 1 of 6	ENSP00000331106.5	Q7Z412-1
	ENSG00000225335	ENST00000607927.2	TSL:6	n.959C>T		non_coding_transcript_exon	Exon 1 of 1
	PEX26	ENST00000399744.8	TSL:1 MANE Select	c.-451G>A		upstream_gene	N/A	ENSP00000382648.4	Q7Z412-1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00392 AC: 819 AN: 209062 Hom.: 13 Cov.: 0 AF XY: 0.00558 AC XY: 647 AN XY: 116044

African (AFR) AF: 0.00 AC: 0 AN: 5278

American (AMR) AF: 0.0000883 AC: 1 AN: 11330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4560

East Asian (EAS) AF: 0.000119 AC: 1 AN: 8414

South Asian (SAS) AF: 0.0181 AC: 792 AN: 43676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 698

European-Non Finnish (NFE) AF: 0.0000258 AC: 3 AN: 116324

Other (OTH) AF: 0.00222 AC: 22 AN: 9922

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000113

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peroxisome biogenesis disorder 7A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.1
DANN	Benign	0.70
PhyloP100		-0.71
PromoterAI		-0.0069	Neutral
Mutation Taster		=300/0	polymorphism

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: rs544836312; hg19: chr22-18560692;