3-179875420-G-T

Variant names:

• chr3-179875420-G-T
• rs149599855
• NM_016559.3:c.563C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016559.3(PEX5L):​c.563C>A​(p.Thr188Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,610,988 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00099 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: PEX5L NM_016559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19

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)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007643044).
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX5L	NM_016559.3	c.563C>A	p.Thr188Asn	missense_variant	Exon 6 of 15	ENST00000467460.6	NP_057643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX5L	ENST00000467460.6	c.563C>A	p.Thr188Asn	missense_variant	Exon 6 of 15	1	NM_016559.3	ENSP00000419975.1

Frequencies

GnomAD3 genomes AF: 0.000988 AC: 150 AN: 151876 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000764 AC: 192 AN: 251460 Hom.: 1 AF XY: 0.000728 AC XY: 99 AN XY: 135910

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00123 AC: 1792 AN: 1458992 Hom.: 4 Cov.: 32 AF XY: 0.00122 AC XY: 883 AN XY: 725844

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.000987 AC: 150 AN: 151996 Hom.: 1 Cov.: 31 AF XY: 0.000942 AC XY: 70 AN XY: 74290

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00115 Hom.: 1

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.00169

EpiControl AF: 0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.563C>A (p.T188N) 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 563, causing the threonine (T) at amino acid position 188 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	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.10	.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0076	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	.;N;.;.;.;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.68	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.46	T;D;D;T;T;T;T;T;D
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;.
Polyphen		0.0030, 0.0060, 0.0	.;B;B;B;.;.;.;.;.
Vest4		0.27
MVP		0.69
MPC		0.47
ClinPred		0.013	T
GERP RS		4.1
Varity_R		0.076
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs149599855; hg19: chr3-179593208;