3-179819883-C-G

Variant names:

• chr3-179819883-C-G
• rs146230186
• NM_016559.3:c.916G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016559.3(PEX5L):​c.916G>C​(p.Val306Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: PEX5L NM_016559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011689782).

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.916G>C	p.Val306Leu	missense	Exon 9 of 15	NP_057643.1	Q8IYB4-1
	PEX5L	NM_001349386.2		c.1081G>C	p.Val361Leu	missense	Exon 10 of 16	NP_001336315.1
	PEX5L	NM_001349387.2		c.988G>C	p.Val330Leu	missense	Exon 10 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.916G>C	p.Val306Leu	missense	Exon 9 of 15	ENSP00000419975.1	Q8IYB4-1
	PEX5L	ENST00000263962.12	TSL:1	c.910G>C	p.Val304Leu	missense	Exon 9 of 15	ENSP00000263962.8	Q8IYB4-2
	PEX5L	ENST00000485199.5	TSL:1	c.811G>C	p.Val271Leu	missense	Exon 8 of 14	ENSP00000418440.1	Q8IYB4-3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000478

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251422 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24 AN XY: 727210

African (AFR) AF: 0.00185 AC: 62 AN: 33474

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111964

Other (OTH) AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74470

African (AFR) AF: 0.00149 AC: 62 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000892 Hom.: 0

Bravo AF: 0.000438

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.73
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.19
Sift	Benign	0.66	T
Sift4G	Benign	0.89	T
Polyphen		0.0010	B
Vest4		0.36
MutPred		0.33		Loss of glycosylation at T307 (P = 0.0838)
MVP		0.66
MPC		0.40
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.60
Mutation Taster		=90/10	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: rs146230186; hg19: chr3-179537671;