chr7-92518266-C-G

Position:

chr7-92518266-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000466.3(PEX1):c.358-11G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,477,148 control chromosomes in the GnomAD database, including 1,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 155 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1093 hom. )

Consequence

PEX1
NM_000466.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001241

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.378

Variant links:

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]

PEX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 7-92518266-C-G is Benign according to our data. Variant chr7-92518266-C-G is described in ClinVar as [Benign]. Clinvar id is 256221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92518266-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
PEX1	NM_000466.3 linkuse as main transcript	c.358-11G>C	splice_polypyrimidine_tract_variant, intron_variant	ENST00000248633.9
PEX1	NM_001282677.2 linkuse as main transcript	c.358-11G>C	splice_polypyrimidine_tract_variant, intron_variant
PEX1	NM_001282678.2 linkuse as main transcript	c.-267-11G>C	splice_polypyrimidine_tract_variant, intron_variant
PEX1	XM_047420472.1 linkuse as main transcript	c.358-11G>C	splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9 linkuse as main transcript	c.358-11G>C	splice_polypyrimidine_tract_variant, intron_variant	1	NM_000466.3	P1	O43933-1
PEX1	ENST00000428214.5 linkuse as main transcript	c.358-11G>C	splice_polypyrimidine_tract_variant, intron_variant	1
PEX1	ENST00000438045.5 linkuse as main transcript	c.273+3836G>C	intron_variant	2			O43933-2
PEX1	ENST00000484913.5 linkuse as main transcript	n.397-11G>C	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0403

AC:

6132

AN:

152008

Hom.:

153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0525

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0231

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00944

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0424

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0417

Gnomad OTH

AF:

0.0311

GnomAD3 exomes

AF:

0.0334

AC:

8393

AN:

251138

Hom.:

173

AF XY:

0.0334

AC XY:

4529

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0531

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00826

Gnomad SAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.0407

Gnomad NFE exome

AF:

0.0432

Gnomad OTH exome

AF:

0.0299

GnomAD4 exome

AF:

0.0380

AC:

50393

AN:

1325022

Hom.:

1093

Cov.:

AF XY:

0.0379

AC XY:

25258

AN XY:

666876

show subpopulations

Gnomad4 AFR exome

AF:

0.0528

Gnomad4 AMR exome

AF:

0.0149

Gnomad4 ASJ exome

AF:

0.0160

Gnomad4 EAS exome

AF:

0.00521

Gnomad4 SAS exome

AF:

0.0261

Gnomad4 FIN exome

AF:

0.0424

Gnomad4 NFE exome

AF:

0.0415

Gnomad4 OTH exome

AF:

0.0341

GnomAD4 genome

AF:

0.0404

AC:

6153

AN:

152126

Hom.:

155

Cov.:

AF XY:

0.0403

AC XY:

2996

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0529

Gnomad4 AMR

AF:

0.0230

Gnomad4 ASJ

AF:

0.0182

Gnomad4 EAS

AF:

0.00985

Gnomad4 SAS

AF:

0.0261

Gnomad4 FIN

AF:

0.0424

Gnomad4 NFE

AF:

0.0417

Gnomad4 OTH

AF:

0.0313

Alfa

AF:

0.0401

Hom.:

Bravo

AF:

0.0383

Asia WGS

AF:

0.0380

AC:

130

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2017	Variant summary: The PEX1 c.358-11G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction the strenghtening of a canonical splice acceptor site site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4339/121280 control chromosomes (85 homozygotes) at a frequency of 0.0357767, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic PEX1 variant (0.003873), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Zellweger spectrum disorders

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.2

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over