rs61750403

Positions:

• chr7-92517734-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000466.3(PEX1):​c.781C>T​(p.Gln261Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX1 NM_000466.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

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 11 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 7-92517734-G-A is Pathogenic according to our data. Variant chr7-92517734-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.781C>T	p.Gln261Ter	stop_gained	5/24	ENST00000248633.9
PEX1	NM_001282677.2	c.781C>T	p.Gln261Ter	stop_gained	5/23
PEX1	NM_001282678.2	c.157C>T	p.Gln53Ter	stop_gained	5/24
PEX1	XM_047420472.1	c.781C>T	p.Gln261Ter	stop_gained	5/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.781C>T	p.Gln261Ter	stop_gained	5/24	1	NM_000466.3	P1
PEX1	ENST00000428214.5	c.781C>T	p.Gln261Ter	stop_gained	5/23	1
PEX1	ENST00000438045.5	c.274-3767C>T		intron_variant		2
PEX1	ENST00000484913.5	n.820C>T		non_coding_transcript_exon_variant	5/24	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.73	D
MutationTaster	Benign	1.0	A;A;N
Vest4		0.56
GERP RS		2.1

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: rs61750403; hg19: chr7-92147048;