rs766020928

chr7-92528434-A-Cchr7-92528434-A-Gchr7-92528434-A-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PVS1 PS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_000466.3(PEX1):c.2T>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000209 in 1,435,574 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PEX1 NM_000466.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.87

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 21 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000466.3 (PEX1) was described as [Likely_pathogenic] in ClinVar as 189106
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-92528434-A-C is Pathogenic according to our data. Variant chr7-92528434-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.2T>G	p.Met1?	start_lost	1/24	ENST00000248633.9
PEX1	NM_001282677.2	c.2T>G	p.Met1?	start_lost	1/23
PEX1	XM_047420472.1	c.2T>G	p.Met1?	start_lost	1/23
PEX1	NM_001282678.2	c.-658T>G		5_prime_UTR_variant	1/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.2T>G	p.Met1?	start_lost	1/24	1	NM_000466.3	P1
PEX1	ENST00000428214.5	c.2T>G	p.Met1?	start_lost	1/23	1
PEX1	ENST00000438045.5	c.2T>G	p.Met1?	start_lost	1/21	2
PEX1	ENST00000484913.5	n.6T>G		non_coding_transcript_exon_variant	1/24	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1435574 Hom.: 0 Cov.: 31 AF XY: 0.00000421 AC XY: 3 AN XY: 711776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000777

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Zellweger spectrum disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PEX1 mRNA. The next in-frame methionine is located at codon 209. Disruption of the initiator codon has been observed in individuals with Zellweger syndrome spectrum disorder (PMID: 21031596). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 371688). -

Peroxisome biogenesis disorder 1B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Nov 19, 2015

- -

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Nov 19, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	31
Dann	Uncertain	0.98
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MutPred		0.98		Gain of MoRF binding (P = 0.0071);Gain of MoRF binding (P = 0.0071);Gain of MoRF binding (P = 0.0071);
MVP		0.93
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.98
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs766020928; hg19: chr7-92157748;