3-179875404-C-T

Variant names:

• chr3-179875404-C-T
• rs1752016864
• NM_016559.3:c.579G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

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 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
PEX5L	NM_016559.3	c.579G>A	p.Met193Ile	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.579G>A	p.Met193Ile	missense_variant	Exon 6 of 15	1	NM_016559.3	ENSP00000419975.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 31

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

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

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

Other links and lift over

dbSNP: rs1752016864; hg19: chr3-179593192;