3-179801904-T-G

Variant names:

• chr3-179801904-T-G
• NM_016559.3:c.1805A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016559.3(PEX5L):​c.1805A>C​(p.Asp602Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX5L NM_016559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• 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]

USP13 (HGNC:12611): (ubiquitin specific peptidase 13) Enables several functions, including BAT3 complex binding activity; chaperone binding activity; and cysteine-type peptidase activity. Involved in several processes, including maintenance of unfolded protein involved in ERAD pathway; regulation of cellular catabolic process; and regulation of transcription, DNA-templated. Acts upstream of or within protein deubiquitination and protein stabilization. Predicted to be located in nucleoplasm. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

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.1805A>C	p.Asp602Ala	missense	Exon 15 of 15	NP_057643.1	Q8IYB4-1
	PEX5L	NM_001349386.2		c.1970A>C	p.Asp657Ala	missense	Exon 16 of 16	NP_001336315.1
	PEX5L	NM_001349387.2		c.1877A>C	p.Asp626Ala	missense	Exon 16 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.1805A>C	p.Asp602Ala	missense	Exon 15 of 15	ENSP00000419975.1	Q8IYB4-1
	PEX5L	ENST00000263962.12	TSL:1	c.1799A>C	p.Asp600Ala	missense	Exon 15 of 15	ENSP00000263962.8	Q8IYB4-2
	PEX5L	ENST00000485199.5	TSL:1	c.1700A>C	p.Asp567Ala	missense	Exon 14 of 14	ENSP00000418440.1	Q8IYB4-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.72
Sift	Benign	0.034	D
Sift4G	Benign	0.086	T
Polyphen		0.99	D
Vest4		0.77
MutPred		0.52		Gain of catalytic residue at D602 (P = 0.2769)
MVP		0.87
MPC		2.8
ClinPred		0.91	D
GERP RS		5.9
Varity_R		0.32
gMVP		0.84
Mutation Taster		=43/57	disease causing

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

hg19: chr3-179519692;