chr7-92528488-G-C

Variant names:

• chr7-92528488-G-C
• rs12386703
• NM_000466.3:c.-53C>G

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.-53C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0789 in 1,510,668 control chromosomes in the GnomAD database, including 4,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (483 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4500 hom.)
• Consequence: PEX1 NM_000466.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.442
• Publications: 12 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]

PEX1 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 1A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, Myriad Women’s Health
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• peroxisome biogenesis disorder 1B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-92528488-G-C is Benign according to our data. Variant chr7-92528488-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000466.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	NM_000466.3	MANE Select	c.-53C>G		5_prime_UTR	Exon 1 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.-53C>G		5_prime_UTR	Exon 1 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.-712C>G		5_prime_UTR	Exon 1 of 24	NP_001269607.1	B4DER6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	ENST00000248633.9	TSL:1 MANE Select	c.-53C>G		5_prime_UTR	Exon 1 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000951788.1		c.-53C>G		5_prime_UTR	Exon 1 of 24	ENSP00000621847.1
	PEX1	ENST00000914336.1		c.-53C>G		5_prime_UTR	Exon 1 of 24	ENSP00000584395.1

Frequencies

GnomAD3 genomes AF: 0.0769 AC: 11705 AN: 152136 Hom.: 485 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0894

Gnomad EAS AF: 0.0309

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0876

Gnomad OTH AF: 0.0828

GnomAD4 exome AF: 0.0791 AC: 107427 AN: 1358414 Hom.: 4500 Cov.: 32 AF XY: 0.0786 AC XY: 52369 AN XY: 665874

African (AFR) AF: 0.0691 AC: 2122 AN: 30728

American (AMR) AF: 0.0609 AC: 2046 AN: 33574

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 1964 AN: 22972

East Asian (EAS) AF: 0.0362 AC: 1283 AN: 35442

South Asian (SAS) AF: 0.0715 AC: 5378 AN: 75220

European-Finnish (FIN) AF: 0.104 AC: 3986 AN: 38266

Middle Eastern (MID) AF: 0.0516 AC: 216 AN: 4182

European-Non Finnish (NFE) AF: 0.0811 AC: 86069 AN: 1061700

Other (OTH) AF: 0.0775 AC: 4363 AN: 56330

GnomAD4 genome AF: 0.0769 AC: 11705 AN: 152254 Hom.: 483 Cov.: 32 AF XY: 0.0769 AC XY: 5724 AN XY: 74438

African (AFR) AF: 0.0676 AC: 2809 AN: 41566

American (AMR) AF: 0.0563 AC: 861 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 310 AN: 3468

East Asian (EAS) AF: 0.0309 AC: 160 AN: 5172

South Asian (SAS) AF: 0.0621 AC: 300 AN: 4828

European-Finnish (FIN) AF: 0.100 AC: 1060 AN: 10596

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0876 AC: 5957 AN: 68010

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.0891 Hom.: 87

Bravo AF: 0.0724

Asia WGS AF: 0.0540 AC: 187 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Peroxisome biogenesis disorder 1A (Zellweger) (2)
-	-	2	Zellweger spectrum disorders (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.7
DANN	Benign	0.57
PhyloP100		-0.44
PromoterAI		0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12386703; hg19: chr7-92157802;