rs61750419

chr7-92501914-G-Achr7-92501914-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP6_Moderate

The NM_000466.3(PEX1):c.2392C>T(p.Arg798Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R798G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.763

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-92501914-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2677620.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant 7-92501914-G-A is Benign according to our data. Variant chr7-92501914-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1494928.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.2392C>T	p.Arg798Cys	missense_variant	14/24	ENST00000248633.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.2392C>T	p.Arg798Cys	missense_variant	14/24	1	NM_000466.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251238 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461468 Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 727068

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Zellweger spectrum disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	16
Dann	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	0.78	D;D;D;D
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.26
MutPred		0.58		.;Gain of catalytic residue at S800 (P = 0.0097);.;
MVP		0.93
MPC		0.37
ClinPred		0.31	T
GERP RS		3.1
Varity_R		0.094
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61750419; hg19: chr7-92131228;