rs116059308

chr2-61032000-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002618.4(PEX13):c.674A>G(p.Asp225Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,612,976 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (9 hom.)
• Consequence: PEX13 NM_002618.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008490264).
• BP6: Variant 2-61032000-A-G is Benign according to our data. Variant chr2-61032000-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 258781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00663 (1010/152244) while in subpopulation AFR AF= 0.0232 (963/41520). AF 95% confidence interval is 0.022. There are 12 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX13	NM_002618.4	c.674A>G	p.Asp225Gly	missense_variant	2/4	ENST00000295030.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX13	ENST00000295030.6	c.674A>G	p.Asp225Gly	missense_variant	2/4	1	NM_002618.4	P1

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1007 AN: 152126 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00163 AC: 410 AN: 251168 Hom.: 3 AF XY: 0.00136 AC XY: 184 AN XY: 135736

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000591 AC: 863 AN: 1460732 Hom.: 9 Cov.: 32 AF XY: 0.000519 AC XY: 377 AN XY: 726666

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00663 AC: 1010 AN: 152244 Hom.: 12 Cov.: 32 AF XY: 0.00619 AC XY: 461 AN XY: 74438

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00184 Hom.: 1

Bravo AF: 0.00707

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 11A (Zellweger) Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Nov 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.022
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.32	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.26
Sift	Benign	0.32	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.22
MVP		0.78
MPC		0.12
ClinPred		0.014	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs116059308; hg19: chr2-61259135; COSMIC: COSV99039012; COSMIC: COSV99039012;