3-179859124-C-G

Variant names:

• chr3-179859124-C-G
• rs201578066
• NM_016559.3:c.760G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016559.3(PEX5L):​c.760G>C​(p.Ala254Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A254T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PEX5L NM_016559.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3322).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5L	NM_016559.3	MANE Select	c.760G>C	p.Ala254Pro	missense	Exon 8 of 15	NP_057643.1	Q8IYB4-1
	PEX5L	NM_001349386.2		c.925G>C	p.Ala309Pro	missense	Exon 9 of 16	NP_001336315.1
	PEX5L	NM_001349387.2		c.832G>C	p.Ala278Pro	missense	Exon 9 of 16	NP_001336316.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5L	ENST00000467460.6	TSL:1 MANE Select	c.760G>C	p.Ala254Pro	missense	Exon 8 of 15	ENSP00000419975.1	Q8IYB4-1
	PEX5L	ENST00000263962.12	TSL:1	c.754G>C	p.Ala252Pro	missense	Exon 8 of 15	ENSP00000263962.8	Q8IYB4-2
	PEX5L	ENST00000485199.5	TSL:1	c.655G>C	p.Ala219Pro	missense	Exon 7 of 14	ENSP00000418440.1	Q8IYB4-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461620 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111792

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.67	N
PhyloP100		1.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.49
Sift	Benign	0.090	T
Sift4G	Benign	0.29	T
Polyphen		0.0080	B
Vest4		0.17
MutPred		0.32		Gain of glycosylation at S253 (P = 0.0151)
MVP		0.76
MPC		0.53
ClinPred		0.81	D
GERP RS		4.9
Varity_R		0.44
gMVP		0.72
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs201578066; hg19: chr3-179576912;