3-179875406-T-C

Variant names:

• chr3-179875406-T-C
• rs1468030868
• NM_016559.3:c.577A>G

Variant summary

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

The NM_001256756.2(PEX5L):​c.1A>G​(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 0.000000685 in 1,460,892 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: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PEX5L NM_001256756.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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.577A>G	p.Met193Val	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.577A>G	p.Met193Val	missense_variant	Exon 6 of 15	1	NM_016559.3	ENSP00000419975.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251470 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726808

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.577A>G (p.M193V) alteration is located in exon 6 (coding exon 6) of the PEX5L gene. This alteration results from a A to G substitution at nucleotide position 577, causing the methionine (M) at amino acid position 193 to be replaced by a valine (V). 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	0.052
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.12	.;T;.;.;.;.;.;.;.;T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	.;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.32	N;N;N;N;N;N;N;N;N;D;D;N
REVEL	Benign	0.22
Sift	Benign	0.32	T;T;T;T;D;T;T;T;T;D;.;D
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T;T;.;.;.
Polyphen		0.0010, 0.0020, 0.0080	.;B;B;B;.;.;.;.;.;.;.;.
Vest4		0.22
MutPred		0.22		.;Gain of glycosylation at S198 (P = 0.0055);.;.;.;.;.;.;.;.;.;.;
MVP		0.55
MPC		0.41
ClinPred		0.059	T
GERP RS		2.2
Varity_R		0.098
gMVP		0.067

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: rs1468030868; hg19: chr3-179593194;