NM_002618.4:c.23C>A

Variant names:

• chr2-61017782-C-A
• rs948971918
• NM_002618.4:c.23C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002618.4(PEX13):​c.23C>A​(p.Pro8His) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,397,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P8L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX13 NM_002618.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.44
• Publications: 0 publications found

Genes affected

PEX13 (HGNC:8855): (peroxisomal biogenesis factor 13) This gene encodes a peroxisomal membrane protein that binds the type 1 peroxisomal targeting signal receptor via a SH3 domain located in the cytoplasm. Mutations and deficiencies in peroxisomal protein importing and peroxisome assembly lead to peroxisomal biogenesis disorders, an example of which is Zellweger syndrome. [provided by RefSeq, Oct 2008]

PUS10 (HGNC:26505): (pseudouridine synthase 10) Pseudouridination, the isomerization of uridine to pseudouridine, is the most common posttranscriptional nucleotide modification found in RNA and is essential for biologic functions such as spliceosome biogenesis. Pseudouridylate synthases, such as PUS10, catalyze pseudouridination of structural RNAs, including transfer, ribosomal, and splicing RNAs. These enzymes also act as RNA chaperones, facilitating the correct folding and assembly of tRNAs (McCleverty et al., 2007 [PubMed 17900615]).[supplied by OMIM, May 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002618.4. 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
	PEX13	NM_002618.4	MANE Select	c.23C>A	p.Pro8His	missense	Exon 1 of 4	NP_002609.1	Q92968
	PUS10	NM_144709.4	MANE Select	c.-16+226G>T		intron	N/A	NP_653310.2	Q3MIT2
	PUS10	NM_001322127.1		c.-623+226G>T		intron	N/A	NP_001309056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX13	ENST00000295030.6	TSL:1 MANE Select	c.23C>A	p.Pro8His	missense	Exon 1 of 4	ENSP00000295030.4	Q92968
	PEX13	ENST00000444100.2	TSL:1	c.23C>A	p.Pro8His	missense	Exon 1 of 2	ENSP00000405184.2	D3YTD3
	PEX13	ENST00000414712.2	TSL:1	c.23C>A	p.Pro8His	missense	Exon 1 of 2	ENSP00000405413.2	G5E9N6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000132 AC: 2 AN: 151312 AF XY: 0.0000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000886

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000174

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397866 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689412

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35878

South Asian (SAS) AF: 0.00 AC: 0 AN: 79130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078816

Other (OTH) AF: 0.00 AC: 0 AN: 57948

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M
PhyloP100		4.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.26		Loss of glycosylation at P8 (P = 4e-04)
MVP		0.86
MPC		0.50
ClinPred		0.94	D
GERP RS		5.3
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.70
gMVP		0.66
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs948971918; hg19: chr2-61244917;