8-76980598-A-T

Position:

• chr8-76980598-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000318.3(PEX2):​c.*2663T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 152,020 control chromosomes in the GnomAD database, including 21,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21286 hom., cov: 32)
  • Exomes 𝑓: 0.44 (2 hom.)
• Consequence: PEX2 NM_000318.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.320

Genes affected

PEX2 (HGNC:9717): (peroxisomal biogenesis factor 2) This gene encodes an integral peroxisomal membrane protein required for peroxisome biogenesis. The protein is thought to be involved in peroxisomal matrix protein import. Mutations in this gene result in one form of Zellweger syndrome and infantile Refsum disease. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-76980598-A-T is Benign according to our data. Variant chr8-76980598-A-T is described in ClinVar as [Benign]. Clinvar id is 363772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX2	NM_000318.3	c.*2663T>A		3_prime_UTR_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2	c.*2663T>A		3_prime_UTR_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2	c.*2663T>A		3_prime_UTR_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2	c.*2663T>A		3_prime_UTR_variant	3/3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX2	ENST00000357039.9	c.*2663T>A		3_prime_UTR_variant	4/4	1	NM_000318.3	ENSP00000349543	P1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77910 AN: 151886 Hom.: 21277 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.551

GnomAD4 exome AF: 0.438 AC: 7 AN: 16 Hom.: 2 Cov.: 0 AF XY: 0.500 AC XY: 4 AN XY: 8

Gnomad4 AFR exome AF: 0.500

Gnomad4 NFE exome AF: 0.429

GnomAD4 genome AF: 0.513 AC: 77938 AN: 152004 Hom.: 21286 Cov.: 32 AF XY: 0.512 AC XY: 38041 AN XY: 74298

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.625

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.613

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.591

Gnomad4 OTH AF: 0.553

Alfa AF: 0.520 Hom.: 2329

Bravo AF: 0.513

Asia WGS AF: 0.518 AC: 1804 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Peroxisome biogenesis disorder 5A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.7
DANN	Benign	0.86

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: rs28435921; hg19: chr8-77892834;