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GeneBe

3-179875375-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016559.3(PEX5L):c.608C>A(p.Thr203Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

PEX5L
NM_016559.3 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17
Variant links:
Genes affected
PEX5L (HGNC:30024): (peroxisomal biogenesis factor 5 like) Enables peroxisome matrix targeting signal-1 binding activity and small GTPase binding activity. Predicted to be involved in protein import into peroxisome matrix, docking and regulation of cAMP-mediated signaling. Predicted to act upstream of or within maintenance of protein location and regulation of membrane potential. Located in cytosol. Part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]
PEX5L-AS1 (HGNC:41251): (PEX5L antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.034867734).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PEX5LNM_016559.3 linkuse as main transcriptc.608C>A p.Thr203Asn missense_variant 6/15 ENST00000467460.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PEX5LENST00000467460.6 linkuse as main transcriptc.608C>A p.Thr203Asn missense_variant 6/151 NM_016559.3 A1Q8IYB4-1
PEX5L-AS1ENST00000466064.1 linkuse as main transcript upstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152130
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
41
AN:
251466
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00149
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000977
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461576
Hom.:
0
Cov.:
32
AF XY:
0.0000591
AC XY:
43
AN XY:
727108
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000604
Gnomad4 ASJ exome
AF:
0.00115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152130
Hom.:
0
Cov.:
31
AF XY:
0.000148
AC XY:
11
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000200
Hom.:
0
Bravo
AF:
0.000276
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 08, 2023The c.608C>A (p.T203N) alteration is located in exon 6 (coding exon 6) of the PEX5L gene. This alteration results from a C to A substitution at nucleotide position 608, causing the threonine (T) at amino acid position 203 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.28
Cadd
Benign
16
Dann
Benign
0.85
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.081
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D;.;D;D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.035
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.63
T
MutationTaster
Benign
0.91
D;D;D;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.61
N;N;N;N;N;N;N;N;N;D;D;N
REVEL
Benign
0.17
Sift
Benign
0.34
T;T;T;T;T;T;T;T;T;D;.;D
Sift4G
Benign
0.50
T;T;T;T;T;T;T;T;T;.;.;.
Polyphen
0.0
.;B;B;B;.;.;.;.;.;.;.;.
Vest4
0.20
MVP
0.74
MPC
0.46
ClinPred
0.028
T
GERP RS
5.0
Varity_R
0.090
gMVP
0.064

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141772500; hg19: chr3-179593163; API