7-92501914-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP6_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

Scores

2
9
8

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.763

Publications

5 publications found
Variant links:
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: PanelApp Australia, 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank MANE Protein UniProt
PEX1NM_000466.3 linkc.2392C>T p.Arg798Cys missense_variant Exon 14 of 24 ENST00000248633.9 NP_000457.1 O43933-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PEX1ENST00000248633.9 linkc.2392C>T p.Arg798Cys missense_variant Exon 14 of 24 1 NM_000466.3 ENSP00000248633.4 O43933-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251238
AF XY:
0.00000736
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39674
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86218
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000288
AC:
32
AN:
1111700
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60382
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41434
American (AMR)
AF:
0.00
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
LINK: link

Submissions by phenotype

Zellweger spectrum disorders Benign:1
Apr 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
DEOGEN2
Uncertain
0.60
.;D;D
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
MutationAssessor
Pathogenic
3.0
.;M;.
PhyloP100
0.76
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
Mutation Taster
=35/65
disease causing

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

Other links and lift over

dbSNP: rs61750419; hg19: chr7-92131228; API