rs74519968

chr7-92507133-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000466.3(PEX1):c.1671-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,612,494 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.016 (208 hom.)
• Consequence: PEX1 NM_000466.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001180
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.21

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-92507133-A-G is Benign according to our data. Variant chr7-92507133-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92507133-A-G is described in Lovd as [Benign]. Variant chr7-92507133-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1926/152328) while in subpopulation NFE AF= 0.0201 (1368/68024). AF 95% confidence interval is 0.0192. There are 22 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.1671-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000248633.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.1671-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000466.3	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1930 AN: 152210 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0119 AC: 2981 AN: 250794 Hom.: 23 AF XY: 0.0115 AC XY: 1562 AN XY: 135600

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00953

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00847

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0159 AC: 23150 AN: 1460166 Hom.: 208 Cov.: 30 AF XY: 0.0156 AC XY: 11304 AN XY: 726534

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.00977

Gnomad4 ASJ exome AF: 0.0186

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00251

Gnomad4 FIN exome AF: 0.00909

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0126 AC: 1926 AN: 152328 Hom.: 22 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74488

Gnomad4 AFR AF: 0.00394

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0173 Hom.: 11

Bravo AF: 0.0121

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0173

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Zellweger spectrum disorders Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	7.7
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
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: rs74519968; hg19: chr7-92136447; COSMIC: COSV104373556; COSMIC: COSV104373556;