rs1554375511

Positions:

• chr7-92517754-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000248633.9(PEX1):​c.760_761insT​(p.Ser254PhefsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX1 ENST00000248633.9 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 7-92517754-G-GA is Pathogenic according to our data. Variant chr7-92517754-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557794.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX1	NM_000466.3	c.760_761insT	p.Ser254PhefsTer5	frameshift_variant	5/24	ENST00000248633.9	NP_000457.1
PEX1	NM_001282677.2	c.760_761insT	p.Ser254PhefsTer5	frameshift_variant	5/23		NP_001269606.1
PEX1	NM_001282678.2	c.136_137insT	p.Ser46PhefsTer5	frameshift_variant	5/24		NP_001269607.1
PEX1	XM_047420472.1	c.760_761insT	p.Ser254PhefsTer5	frameshift_variant	5/23		XP_047276428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.760_761insT	p.Ser254PhefsTer5	frameshift_variant	5/24	1	NM_000466.3	ENSP00000248633	P1
PEX1	ENST00000428214.5	c.760_761insT	p.Ser254PhefsTer5	frameshift_variant	5/23	1		ENSP00000394413
PEX1	ENST00000438045.5	c.274-3788_274-3787insT		intron_variant		2		ENSP00000410438
PEX1	ENST00000484913.5	n.799_800insT		non_coding_transcript_exon_variant	5/24	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554375511; hg19: chr7-92147068;