7-92499847-CAAAA-CAA

Variant names:

• chr7-92499847-CAA-C
• rs5885806
• NM_000466.3:c.2584-11_2584-10delTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000466.3(PEX1):​c.2584-11_2584-10delTT variant causes a intron change. The variant allele was found at a frequency of 0.0673 in 1,106,330 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 0)
  • Exomes 𝑓: 0.077 (10 hom.)
• Consequence: PEX1 NM_000466.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• 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: Myriad Women's Health, Ambry Genetics
• 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-CAA-C is Benign according to our data. Variant chr7-92499847-CAA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194603.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00334 (487/145992) while in subpopulation NFE AF = 0.00478 (317/66316). AF 95% confidence interval is 0.00435. There are 1 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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.2584-11_2584-10delTT		intron	N/A	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.2413-11_2413-10delTT		intron	N/A	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.1960-11_1960-10delTT		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.2584-11_2584-10delTT		intron	N/A	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.2413-11_2413-10delTT		intron	N/A	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.2584-11_2584-10delTT		intron	N/A	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 487 AN: 145898 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000592

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.000429

Gnomad FIN AF: 0.00647

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00250

GnomAD2 exomes AF: 0.0769 AC: 11839 AN: 153898 AF XY: 0.0807

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.0838

Gnomad ASJ exome AF: 0.0826

Gnomad EAS exome AF: 0.0565

Gnomad FIN exome AF: 0.0755

Gnomad NFE exome AF: 0.0777

Gnomad OTH exome AF: 0.0917

GnomAD4 exome AF: 0.0771 AC: 74006 AN: 960338 Hom.: 10 AF XY: 0.0779 AC XY: 36997 AN XY: 474826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0376 AC: 965 AN: 25678

American (AMR) AF: 0.0805 AC: 2494 AN: 30992

Ashkenazi Jewish (ASJ) AF: 0.0777 AC: 1314 AN: 16910

East Asian (EAS) AF: 0.0503 AC: 1477 AN: 29376

South Asian (SAS) AF: 0.103 AC: 5183 AN: 50416

European-Finnish (FIN) AF: 0.0821 AC: 2898 AN: 35290

Middle Eastern (MID) AF: 0.0547 AC: 233 AN: 4256

European-Non Finnish (NFE) AF: 0.0775 AC: 56391 AN: 727292

Other (OTH) AF: 0.0760 AC: 3051 AN: 40128

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00334 AC: 487 AN: 145992 Hom.: 1 Cov.: 0 AF XY: 0.00312 AC XY: 222 AN XY: 71158

African (AFR) AF: 0.00120 AC: 47 AN: 39296

American (AMR) AF: 0.00353 AC: 52 AN: 14742

Ashkenazi Jewish (ASJ) AF: 0.000592 AC: 2 AN: 3376

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4970

South Asian (SAS) AF: 0.000429 AC: 2 AN: 4660

European-Finnish (FIN) AF: 0.00647 AC: 61 AN: 9434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00478 AC: 317 AN: 66316

Other (OTH) AF: 0.00247 AC: 5 AN: 2024

Alfa AF: 0.134 Hom.: 1774

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Zellweger spectrum disorders (2)
-	-	1	not provided (1)
-	1	-	Peroxisome biogenesis disorder 1A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5885806;

hg19: chr7-92129161;