Genetic Variant PEX1:c.-137T>C (chr7-92528572-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000466.3(PEX1):c.-137T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,317,404 control chromosomes in the GnomAD database, including 9,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1163 hom., cov: 32)

Exomes 𝑓: 0.12 ( 8418 hom. )

Consequence

PEX1
NM_000466.3 upstream_gene

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.65

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:

RBM48 (HGNC:21785): (RNA binding motif protein 48) Predicted to enable RNA binding activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RBM48 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 7-92528572-A-G is Benign according to our data. Variant chr7-92528572-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.-137T>C		upstream_gene_variant		ENST00000248633.9	NP_000457.1	O43933-1
RBM48	NM_032120.4 link	c.-242A>G		upstream_gene_variant		ENST00000265732.10	NP_115496.2	Q5RL73-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9 link	c.-137T>C		upstream_gene_variant		1	NM_000466.3	ENSP00000248633.4		O43933-1
RBM48	ENST00000265732.10 link	c.-242A>G		upstream_gene_variant		1	NM_032120.4	ENSP00000265732.5		Q5RL73-1

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18416

AN:

151832

Hom.:

1158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.0782

Gnomad AMR

AF:

0.0810

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.0415

Gnomad SAS

AF:

0.0882

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.118

GnomAD4 exome

AF:

0.117

AC:

136454

AN:

1165458

Hom.:

8418

Cov.:

AF XY:

0.116

AC XY:

66043

AN XY:

568846

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.0795

Gnomad4 ASJ exome

AF:

0.0992

Gnomad4 EAS exome

AF:

0.0410

Gnomad4 SAS exome

AF:

0.0961

Gnomad4 FIN exome

AF:

0.145

Gnomad4 NFE exome

AF:

0.121

Gnomad4 OTH exome

AF:

0.113

GnomAD4 genome

AF:

0.121

AC:

18447

AN:

151946

Hom.:

1163

Cov.:

AF XY:

0.121

AC XY:

8993

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.134

Gnomad4 AMR

AF:

0.0806

Gnomad4 ASJ

AF:

0.108

Gnomad4 EAS

AF:

0.0418

Gnomad4 SAS

AF:

0.0879

Gnomad4 FIN

AF:

0.143

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.123

Hom.:

1142

Bravo

AF:

0.115

Asia WGS

AF:

0.0940

AC:

328

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Zellweger spectrum disorders

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

May 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Benign:1

Jul 01, 2021

Genome-Nilou Lab

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

-0.82

CADD

Benign

1.5

DANN

Benign

0.34

Splicing

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