2-61017692-C-T

Variant names:

• chr2-61017692-C-T
• rs571713221
• ENST00000444100.2:c.-68C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000401576.1(PEX13):​c.-64-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,295,270 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PEX13 ENST00000401576.1 splice_region, intron
• Scores: Splicing: ADA: 0.0001492
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.467
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00188 (286/152322) while in subpopulation AMR AF = 0.00144 (22/15300). AF 95% confidence interval is 0.000973. There are 10 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000401576.1. 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
	PUS10	NM_144709.4	MANE Select	c.-16+316G>A		intron	N/A	NP_653310.2	Q3MIT2
	PUS10	NM_001322127.1		c.-623+316G>A		intron	N/A	NP_001309056.1
	PEX13	NM_002618.4	MANE Select	c.-68C>T		upstream_gene	N/A	NP_002609.1	Q92968

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX13	ENST00000444100.2	TSL:1	c.-68C>T		5_prime_UTR	Exon 1 of 2	ENSP00000405184.2	D3YTD3
	PUS10	ENST00000316752.11	TSL:1 MANE Select	c.-16+316G>A		intron	N/A	ENSP00000326003.6	Q3MIT2
	PEX13	ENST00000401576.1	TSL:1	c.-64-4C>T		splice_region intron	N/A	ENSP00000384738.1	B5MBY9

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152204 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00113 AC: 1286 AN: 1142948 Hom.: 1 Cov.: 15 AF XY: 0.00108 AC XY: 613 AN XY: 569748

African (AFR) AF: 0.000112 AC: 3 AN: 26706

American (AMR) AF: 0.00126 AC: 42 AN: 33256

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 233 AN: 22360

East Asian (EAS) AF: 0.00 AC: 0 AN: 34462

South Asian (SAS) AF: 0.00 AC: 0 AN: 72454

European-Finnish (FIN) AF: 0.000171 AC: 8 AN: 46898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3680

European-Non Finnish (NFE) AF: 0.00109 AC: 929 AN: 854222

Other (OTH) AF: 0.00145 AC: 71 AN: 48910

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152322 Hom.: 10 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74476

African (AFR) AF: 0.000289 AC: 12 AN: 41578

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00250

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peroxisome biogenesis disorder 1A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.9
DANN	Benign	0.87
PhyloP100		0.47
PromoterAI		0.13	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.060		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: rs571713221; hg19: chr2-61244827;