1-2405123-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002617.4(PEX10):c.*643C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 160,804 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (6 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: PEX10 NM_002617.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.929

Genes affected

PEX10 (HGNC:8851): (peroxisomal biogenesis factor 10) This gene encodes a protein involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane. Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

RER1 (HGNC:30309): (retention in endoplasmic reticulum sorting receptor 1) The protein encoded by this gene is a multi-pass membrane protein that is localized to the golgi apparatus. It is involved in the retention of endoplasmic reticulum (ER) membrane proteins in the ER and retrieval of ER membrane proteins from the early Golgi compartment to facilitate gamma-secretase complex assembly. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00181 (276/152346) while in subpopulation EAS AF= 0.00636 (33/5188). AF 95% confidence interval is 0.00465. There are 6 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX10	NM_002617.4	c.*643C>T		3_prime_UTR_variant	6/6	ENST00000447513.7
RER1	NM_007033.5	c.*1999G>A		3_prime_UTR_variant	7/7	ENST00000605895.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX10	ENST00000447513.7	c.*643C>T		3_prime_UTR_variant	6/6	1	NM_002617.4	P4
RER1	ENST00000605895.6	c.*1999G>A		3_prime_UTR_variant	7/7	1	NM_007033.5	P1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152228 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.00166 AC: 14 AN: 8458 Hom.: 0 Cov.: 0 AF XY: 0.00177 AC XY: 8 AN XY: 4518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00250

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0314

Gnomad4 NFE exome AF: 0.000455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152346 Hom.: 6 Cov.: 34 AF XY: 0.00256 AC XY: 191 AN XY: 74500

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00636

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.000419

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.7
Dann	Benign	0.73

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: rs150136015; hg19: chr1-2336562;