rs41310349

Variant names:

• chr1-2405080-G-C
• rs41310349
• NM_002617.4:c.*686C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002617.4(PEX10):​c.*686C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 160,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0042 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0051 (1 hom.)
• Consequence: PEX10 NM_002617.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.50
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00423 (644/152348) while in subpopulation NFE AF = 0.00635 (432/68026). AF 95% confidence interval is 0.00586. There are 0 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX10	NM_002617.4	c.*686C>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000447513.7	NP_002608.1
RER1	NM_007033.5	c.*1956G>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000605895.6	NP_008964.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX10	ENST00000447513.7	c.*686C>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_002617.4	ENSP00000407922.2
RER1	ENST00000605895.6	c.*1956G>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_007033.5	ENSP00000475168.1

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 644 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.00508 AC: 43 AN: 8460 Hom.: 1 Cov.: 0 AF XY: 0.00468 AC XY: 21 AN XY: 4490

African (AFR) AF: 0.00 AC: 0 AN: 24

American (AMR) AF: 0.00365 AC: 7 AN: 1916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 50

East Asian (EAS) AF: 0.00 AC: 0 AN: 348

South Asian (SAS) AF: 0.00 AC: 0 AN: 990

European-Finnish (FIN) AF: 0.00221 AC: 1 AN: 452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00801 AC: 35 AN: 4368

Other (OTH) AF: 0.00 AC: 0 AN: 308

GnomAD4 genome AF: 0.00423 AC: 644 AN: 152348 Hom.: 0 Cov.: 34 AF XY: 0.00397 AC XY: 296 AN XY: 74506

African (AFR) AF: 0.00142 AC: 59 AN: 41590

American (AMR) AF: 0.00621 AC: 95 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00635 AC: 432 AN: 68026

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00503 Hom.: 0

Bravo AF: 0.00370

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 6A (Zellweger) Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.90
CADD	Benign	0.089
DANN	Benign	0.47
PhyloP100		-2.5
Mutation Taster		=100/0	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: rs41310349; hg19: chr1-2336519;