chr7-92499847-CA-C

Variant names:

• chr7-92499847-CA-C
• rs5885806
• NM_000466.3:c.2584-10delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000466.3(PEX1):​c.2584-10delT variant causes a intron change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.75 (40360 hom., cov: 0)
  • Exomes 𝑓: 0.59 (117822 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX1 NM_000466.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 5.05
• Publications: 6 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

ENSG00000244055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 7-92499847-CA-C is Benign according to our data. Variant chr7-92499847-CA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360922.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.828 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.2584-10delT		intron	N/A	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.2413-10delT		intron	N/A	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.1960-10delT		intron	N/A	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.2584-10delT		intron	N/A	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.2413-10delT		intron	N/A	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.2584-10delT		intron	N/A	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.745 AC: 108881 AN: 146078 Hom.: 40356 Cov.: 0

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.776

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.753

GnomAD2 exomes AF: 0.597 AC: 91804 AN: 153898 AF XY: 0.596

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.566

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.584

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.585 AC: 683458 AN: 1168006 Hom.: 117822 Cov.: 0 AF XY: 0.584 AC XY: 342329 AN XY: 586582

African (AFR) AF: 0.510 AC: 14125 AN: 27696

American (AMR) AF: 0.556 AC: 21156 AN: 38068

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 12363 AN: 22122

East Asian (EAS) AF: 0.547 AC: 18653 AN: 34076

South Asian (SAS) AF: 0.568 AC: 40829 AN: 71876

European-Finnish (FIN) AF: 0.583 AC: 25998 AN: 44584

Middle Eastern (MID) AF: 0.647 AC: 3201 AN: 4950

European-Non Finnish (NFE) AF: 0.593 AC: 518817 AN: 875486

Other (OTH) AF: 0.576 AC: 28316 AN: 49148

GnomAD4 genome AF: 0.745 AC: 108923 AN: 146176 Hom.: 40360 Cov.: 0 AF XY: 0.746 AC XY: 53145 AN XY: 71248

African (AFR) AF: 0.624 AC: 24523 AN: 39282

American (AMR) AF: 0.768 AC: 11319 AN: 14734

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2635 AN: 3382

East Asian (EAS) AF: 0.689 AC: 3426 AN: 4970

South Asian (SAS) AF: 0.851 AC: 3962 AN: 4658

European-Finnish (FIN) AF: 0.782 AC: 7449 AN: 9528

Middle Eastern (MID) AF: 0.778 AC: 224 AN: 288

European-Non Finnish (NFE) AF: 0.800 AC: 53140 AN: 66432

Other (OTH) AF: 0.754 AC: 1521 AN: 2018

Alfa AF: 0.585 Hom.: 1774

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	1	Peroxisome biogenesis disorder 1A (Zellweger) (2)
-	-	2	Zellweger spectrum disorders (2)
-	-	1	Heimler syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	Peroxisome biogenesis disorder (1)
-	-	1	Peroxisome biogenesis disorder 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=100/0	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: rs5885806; hg19: chr7-92129161;