rs786204704

Variant names:

• chr7-92528433-C-T
• rs786204704
• NM_000466.3:c.3G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001282678.2(PEX1):​c.-657G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000139 in 1,437,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX1 NM_001282678.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.60

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 7-92528433-C-T is Pathogenic according to our data. Variant chr7-92528433-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92528433-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.3G>A	p.Met1?	start_lost	Exon 1 of 24	ENST00000248633.9	NP_000457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.3G>A	p.Met1?	start_lost	Exon 1 of 24	1	NM_000466.3	ENSP00000248633.4
PEX1	ENST00000428214.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 23	1		ENSP00000394413.1
PEX1	ENST00000438045.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 21	2		ENSP00000410438.1
PEX1	ENST00000484913.5	n.7G>A		non_coding_transcript_exon_variant	Exon 1 of 24	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437090 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 712614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Zellweger spectrum disorders Pathogenic:1

Dec 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PEX1 mRNA. The next in-frame methionine is located at codon 209. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with Zellweger spectrum disorder (PMID: 21031596, 28468868). ClinVar contains an entry for this variant (Variation ID: 189106). For these reasons, this variant has been classified as Pathogenic. -

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1

Dec 24, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	.;T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.69	D
PROVEAN	Benign	-0.36	N;N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.69	.;P;.
Vest4		0.97
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0721);Gain of catalytic residue at M1 (P = 0.0721);Gain of catalytic residue at M1 (P = 0.0721);
MVP		0.90
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.57

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: rs786204704; hg19: chr7-92157747; COSMIC: COSV50395507; COSMIC: COSV50395507;