PEX1 p.Gly593Arg

Variant names:

• chr7-92507020-C-G
• NM_000466.3:c.1777G>C
• PEX1 p.Gly593Arg

Your query was ambiguous. Multiple possible variants found:

• chr7-92507020-C-G
• chr7-92507020-C-T
• chr7-92507018-TCC-ACG
• chr7-92507018-TCC-GCG
• chr7-92507018-TCC-CCG
• chr7-92507018-TCC-CCT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_Strong PM2 PP3_Strong

The NM_000466.3(PEX1):​c.1777G>C​(p.Gly593Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.90
• 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: 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: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000466.3 (PEX1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

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.1777G>C	p.Gly593Arg	missense	Exon 10 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.1777G>C	p.Gly593Arg	missense	Exon 10 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.1153G>C	p.Gly385Arg	missense	Exon 10 of 24	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.1777G>C	p.Gly593Arg	missense	Exon 10 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.1777G>C	p.Gly593Arg	missense	Exon 10 of 23	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.1777G>C	p.Gly593Arg	missense	Exon 10 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.049	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.88
gMVP		0.93
Mutation Taster		=5/95	disease causing

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

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

Other links and lift over

hg19: chr7-92136334;