3-179875404-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001256756.2(PEX5L):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

PEX5L
NM_001256756.2 start_lost

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14
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 Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 91 codons. Genomic position: 179819952. Lost 0.208 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PEX5LNM_016559.3 linkc.579G>A p.Met193Ile missense_variant Exon 6 of 15 ENST00000467460.6 NP_057643.1 Q8IYB4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PEX5LENST00000467460.6 linkc.579G>A p.Met193Ile missense_variant Exon 6 of 15 1 NM_016559.3 ENSP00000419975.1 Q8IYB4-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74272
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
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

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 17, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.579G>A (p.M193I) alteration is located in exon 6 (coding exon 6) of the PEX5L gene. This alteration results from a G to A substitution at nucleotide position 579, causing the methionine (M) at amino acid position 193 to be replaced by an isoleucine (I). 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
0.088
BayesDel_addAF
Uncertain
0.035
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
19
DANN
Benign
0.97
DEOGEN2
Benign
0.13
.;T;.;.;.;.;.;.;.;T;T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.036
FATHMM_MKL
Benign
0.60
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;.;D;D;D;D
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.14
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
0.0
.;N;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.46
N;N;N;N;N;N;N;N;N;D;D;N
REVEL
Benign
0.21
Sift
Benign
0.23
T;T;T;T;D;T;T;T;T;D;.;D
Sift4G
Benign
0.40
T;T;T;T;T;T;T;T;T;.;.;.
Polyphen
0.0020, 0.0040, 0.037
.;B;B;B;.;.;.;.;.;.;.;.
Vest4
0.32
MutPred
0.23
.;Gain of glycosylation at S198 (P = 0.0055);.;.;.;.;.;.;.;.;.;.;
MVP
0.60
MPC
0.45
ClinPred
0.61
D
GERP RS
5.0
Varity_R
0.15
gMVP
0.056

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1752016864; hg19: chr3-179593192; API