NM_000466.3:c.-137T>C

Variant names:

• chr7-92528572-A-G
• rs12386601
• NM_000466.3:c.-137T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.65
• Publications: 17 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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	c.-137T>C		upstream_gene_variant		ENST00000248633.9	NP_000457.1
RBM48	NM_032120.4	c.-242A>G		upstream_gene_variant		ENST00000265732.10	NP_115496.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18416 AN: 151832 Hom.: 1158 Cov.: 32

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.: 17 AF XY: 0.116 AC XY: 66043 AN XY: 568846

African (AFR) AF: 0.136 AC: 3430 AN: 25196

American (AMR) AF: 0.0795 AC: 1521 AN: 19136

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 1767 AN: 17806

East Asian (EAS) AF: 0.0410 AC: 1345 AN: 32792

South Asian (SAS) AF: 0.0961 AC: 5766 AN: 60012

European-Finnish (FIN) AF: 0.145 AC: 4494 AN: 30920

Middle Eastern (MID) AF: 0.0760 AC: 254 AN: 3342

European-Non Finnish (NFE) AF: 0.121 AC: 112299 AN: 926860

Other (OTH) AF: 0.113 AC: 5578 AN: 49394

GnomAD4 genome AF: 0.121 AC: 18447 AN: 151946 Hom.: 1163 Cov.: 32 AF XY: 0.121 AC XY: 8993 AN XY: 74286

African (AFR) AF: 0.134 AC: 5579 AN: 41480

American (AMR) AF: 0.0806 AC: 1232 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3462

East Asian (EAS) AF: 0.0418 AC: 215 AN: 5138

South Asian (SAS) AF: 0.0879 AC: 421 AN: 4792

European-Finnish (FIN) AF: 0.143 AC: 1510 AN: 10552

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8775 AN: 67920

Other (OTH) AF: 0.117 AC: 248 AN: 2112

Alfa AF: 0.121 Hom.: 1444

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

Submissions by phenotype

Zellweger spectrum disorders Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

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
PhyloP100		-1.7
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12386601; hg19: chr7-92157886;