rs61750406

Variant names:

• chr7-92517406-AT-A
• rs61750406
• NM_000466.3:c.1108delA

Your query was ambiguous. Multiple possible variants found:

• chr7-92517406-AT-A
• chr7-92517406-AT-ATT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000466.3(PEX1):​c.1108delA​(p.Ile370LeufsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,444,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX1 NM_000466.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.542
• Publications: 10 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: PanelApp Australia, 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92517406-AT-A is Pathogenic according to our data. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92517406-AT-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 371779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.1108delA	p.Ile370LeufsTer17	frameshift_variant	Exon 5 of 24	ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.1108delA	p.Ile370LeufsTer17	frameshift_variant	Exon 5 of 23		NP_001269606.1
PEX1	NM_001282678.2	c.484delA	p.Ile162LeufsTer17	frameshift_variant	Exon 5 of 24		NP_001269607.1
PEX1	XM_047420472.1	c.1108delA	p.Ile370LeufsTer17	frameshift_variant	Exon 5 of 23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.1108delA	p.Ile370LeufsTer17	frameshift_variant	Exon 5 of 24	1	NM_000466.3	ENSP00000248633.4

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150684 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000449 AC: 11 AN: 244980 AF XY: 0.0000528

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000596

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.0000540

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.0000464 AC: 67 AN: 1444688 Hom.: 0 Cov.: 33 AF XY: 0.0000501 AC XY: 36 AN XY: 719120

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

African (AFR) AF: 0.000121 AC: 4 AN: 33100

American (AMR) AF: 0.00 AC: 0 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85586

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 52832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000474 AC: 52 AN: 1097974

Other (OTH) AF: 0.0000167 AC: 1 AN: 59730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000133 AC: 2 AN: 150684 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73498

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

African (AFR) AF: 0.00 AC: 0 AN: 41020

American (AMR) AF: 0.0000664 AC: 1 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67608

Other (OTH) AF: 0.00 AC: 0 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000738 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:2

Sep 05, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Zellweger spectrum disorders Pathogenic:1

Oct 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ile370Leufs*17) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PEX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 371779). For these reasons, this variant has been classified as Pathogenic. -

Heimler syndrome 1 Pathogenic:1

Mar 18, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Apr 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 1B Pathogenic:1

Oct 07, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.54
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61750406; hg19: chr7-92146720; COSMIC: COSV50395420; COSMIC: COSV50395420;