rs74350038

Variant names:

• chr2-61048636-C-G
• rs74350038
• NM_002618.4:c.1078C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002618.4(PEX13):​c.1078C>G​(p.Leu360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,614,022 control chromosomes in the GnomAD database, including 1,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L360L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (72 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1032 hom.)
• Consequence: PEX13 NM_002618.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.626
• Publications: 17 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]

PEX13 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 11A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• peroxisome biogenesis disorder 11B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025173426).
• BP6: Variant 2-61048636-C-G is Benign according to our data. Variant chr2-61048636-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 336670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0238 (3630/152278) while in subpopulation NFE AF = 0.0386 (2627/68022). AF 95% confidence interval is 0.0374. There are 72 homozygotes in GnomAd4. There are 1716 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX13	NM_002618.4	MANE Select	c.1078C>G	p.Leu360Val	missense	Exon 4 of 4	NP_002609.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX13	ENST00000295030.6	TSL:1 MANE Select	c.1078C>G	p.Leu360Val	missense	Exon 4 of 4	ENSP00000295030.4
	PEX13	ENST00000920043.1		c.1177C>G	p.Leu393Val	missense	Exon 5 of 5	ENSP00000590102.1
	PEX13	ENST00000902278.1		c.1099C>G	p.Leu367Val	missense	Exon 4 of 4	ENSP00000572337.1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3627 AN: 152160 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.00736

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0239 AC: 5998 AN: 251474 AF XY: 0.0239

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0347 AC: 50785 AN: 1461744 Hom.: 1032 Cov.: 31 AF XY: 0.0341 AC XY: 24797 AN XY: 727168

African (AFR) AF: 0.00520 AC: 174 AN: 33480

American (AMR) AF: 0.0132 AC: 590 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00819 AC: 214 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00926 AC: 799 AN: 86258

European-Finnish (FIN) AF: 0.0300 AC: 1602 AN: 53420

Middle Eastern (MID) AF: 0.0222 AC: 128 AN: 5768

European-Non Finnish (NFE) AF: 0.0409 AC: 45485 AN: 1111878

Other (OTH) AF: 0.0297 AC: 1792 AN: 60394

GnomAD4 genome AF: 0.0238 AC: 3630 AN: 152278 Hom.: 72 Cov.: 33 AF XY: 0.0230 AC XY: 1716 AN XY: 74454

African (AFR) AF: 0.00734 AC: 305 AN: 41560

American (AMR) AF: 0.0181 AC: 276 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0266 AC: 282 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0386 AC: 2627 AN: 68022

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0340 Hom.: 78

Bravo AF: 0.0225

TwinsUK AF: 0.0429 AC: 159

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0379 AC: 326

ExAC AF: 0.0241 AC: 2922

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0371

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Peroxisome biogenesis disorder 11A (Zellweger) (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.3
DANN	Benign	0.049
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		-0.63
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.15
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.085
ClinPred		0.000071	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.19
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74350038; hg19: chr2-61275771; COSMIC: COSV54371007;