rs76708142

Variant names:

• chr12-7202673-T-C
• rs76708142
• NM_001351132.2:c.815T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-7202673-T-C
• chr12-7202673-T-A
• chr12-7202673-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001351132.2(PEX5):​c.815T>C​(p.Met272Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,613,998 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (83 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (97 hom.)
• Consequence: PEX5 NM_001351132.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.46
• Publications: 8 publications found

Genes affected

PEX5 (HGNC:9719): (peroxisomal biogenesis factor 5) The product of this gene binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of neonatal adrenoleukodystrophy (NALD), a cause of Zellweger syndrome (ZWS) as well as may be a cause of infantile Refsum disease (IRD). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

PEX5 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 2A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• peroxisome biogenesis disorder 2B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• rhizomelic chondrodysplasia punctata type 5

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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=0.0031735003).
• BP6: Variant 12-7202673-T-C is Benign according to our data. Variant chr12-7202673-T-C is described in ClinVar as Benign. ClinVar VariationId is 235376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351132.2. 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
	PEX5	NM_001351132.2	MANE Select	c.815T>C	p.Met272Thr	missense	Exon 9 of 16	NP_001338061.1	P50542-1
	PEX5	NM_001131023.2		c.860T>C	p.Met287Thr	missense	Exon 9 of 16	NP_001124495.1	P50542-4
	PEX5	NM_001131025.2		c.815T>C	p.Met272Thr	missense	Exon 9 of 16	NP_001124497.1	A0A0S2Z4H1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX5	ENST00000675855.1	MANE Select	c.815T>C	p.Met272Thr	missense	Exon 9 of 16	ENSP00000502374.1	P50542-1
	PEX5	ENST00000420616.6	TSL:1	c.815T>C	p.Met272Thr	missense	Exon 9 of 16	ENSP00000410159.2	P50542-1
	PEX5	ENST00000266564.7	TSL:1	c.815T>C	p.Met272Thr	missense	Exon 8 of 15	ENSP00000266564.3	P50542-3

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3109 AN: 152082 Hom.: 81 Cov.: 32

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00548

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00746 AC: 1877 AN: 251494 AF XY: 0.00608

Gnomad AFR exome AF: 0.0591

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00570

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00573 AC: 8372 AN: 1461798 Hom.: 97 Cov.: 31 AF XY: 0.00539 AC XY: 3918 AN XY: 727200

African (AFR) AF: 0.0587 AC: 1964 AN: 33472

American (AMR) AF: 0.00474 AC: 212 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00181 AC: 156 AN: 86256

European-Finnish (FIN) AF: 0.00202 AC: 108 AN: 53416

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.00492 AC: 5475 AN: 1111934

Other (OTH) AF: 0.00695 AC: 420 AN: 60394

GnomAD4 genome AF: 0.0205 AC: 3121 AN: 152200 Hom.: 83 Cov.: 32 AF XY: 0.0202 AC XY: 1500 AN XY: 74406

African (AFR) AF: 0.0610 AC: 2530 AN: 41496

American (AMR) AF: 0.0114 AC: 174 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00548 AC: 373 AN: 68020

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.0122 Hom.: 45

Bravo AF: 0.0231

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.0531 AC: 234

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00876 AC: 1063

EpiCase AF: 0.00436

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Peroxisome biogenesis disorder 2A (Zellweger) (1)
-	-	1	Peroxisome biogenesis disorder 2B (1)
-	-	1	Peroxisome biogenesis disorder 2B;C3550273:Peroxisome biogenesis disorder 2A (Zellweger);C4225237:Rhizomelic chondrodysplasia punctata type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.22	N
REVEL	Uncertain	0.40
Sift	Benign	0.42	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.27
MVP		0.78
MPC		0.31
ClinPred		0.0016	T
GERP RS		4.5
Varity_R		0.022
gMVP		0.33
Mutation Taster		=99/1	polymorphism (auto)

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

dbSNP: rs76708142; hg19: chr12-7355269;