chr7-92522101-C-T

Variant names:

• chr7-92522101-C-T
• rs1554376597
• NM_000466.3:c.273+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000466.3(PEX1):​c.273+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000205 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PEX1 NM_000466.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.17
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.037383176 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92522101-C-T is Pathogenic according to our data. Variant chr7-92522101-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 558237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.273+1G>A		splice_donor intron	N/A	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.273+1G>A		splice_donor intron	N/A	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.-387+1G>A		splice_donor 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.273+1G>A		splice_donor intron	N/A	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.273+1G>A		splice_donor intron	N/A	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.273+1G>A		splice_donor intron	N/A	ENSP00000621847.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461564 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111744

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Zellweger spectrum disorders (2)
1	-	-	Heimler syndrome 1 (1)
1	-	-	Peroxisome biogenesis disorder 1A (Zellweger) (1)
1	-	-	Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		6.2
GERP RS		6.0
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs1554376597; hg19: chr7-92151415;