chr22-18078014-G-C

Variant names:

• chr22-18078014-G-C
• rs138787474
• NM_001127649.3:c.-363G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127649.3(PEX26):​c.-363G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 465,018 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (15 hom.)
• Consequence: PEX26 NM_001127649.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0610

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-18078014-G-C is Benign according to our data. Variant chr22-18078014-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 340748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX26	NM_001127649.3	c.-363G>C		5_prime_UTR_variant	Exon 1 of 5	ENST00000399744.8	NP_001121121.1
PEX26	NM_017929.6	c.-115G>C		5_prime_UTR_variant	Exon 1 of 6		NP_060399.1
PEX26	NM_001199319.2	c.-115G>C		5_prime_UTR_variant	Exon 1 of 5		NP_001186248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX26	ENST00000399744	c.-363G>C		5_prime_UTR_variant	Exon 1 of 5	1	NM_001127649.3	ENSP00000382648.4
ENSG00000288683	ENST00000474897.6	n.-115G>C		non_coding_transcript_exon_variant	Exon 1 of 9	5		ENSP00000434235.2
ENSG00000288683	ENST00000474897.6	n.-115G>C		5_prime_UTR_variant	Exon 1 of 9	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2481 AN: 152168 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00235 AC: 736 AN: 312738 Hom.: 15 Cov.: 0 AF XY: 0.00189 AC XY: 334 AN XY: 177014

Gnomad4 AFR exome AF: 0.0563

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000257

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.0163 AC: 2489 AN: 152280 Hom.: 59 Cov.: 32 AF XY: 0.0156 AC XY: 1161 AN XY: 74462

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0000713 Hom.: 0

Bravo AF: 0.0188

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 7A (Zellweger) Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.74
DANN	Benign	0.70

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: rs138787474; hg19: chr22-18560780;