12-7202673-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001351132.2(PEX5):​c.815T>G​(p.Met272Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. M272T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX5 NM_001351132.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09565812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX5	NM_001351132.2	c.815T>G	p.Met272Arg	missense_variant	Exon 9 of 16	ENST00000675855.1	NP_001338061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX5	ENST00000675855.1	c.815T>G	p.Met272Arg	missense_variant	Exon 9 of 16		NM_001351132.2	ENSP00000502374.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251494 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 45

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T;.;.;.;T;T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	.;T;T;T;T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.096	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.3	L;.;.;.;L;.;.;L
PhyloP100		1.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.48	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.34	T;T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;B;B;.;B
Vest4		0.51
MutPred		0.36		.;.;.;.;.;Gain of disorder (P = 0.0444);.;.;
MVP		0.78
MPC		0.40
ClinPred		0.084	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.56
Mutation Taster		=86/14	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: rs76708142; hg19: chr12-7355269;