6-136822571-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000541292.6(PEX7):c.-95T>C variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 1,144,364 control chromosomes in the GnomAD database, including 178,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19992 hom., cov: 35)
  • Exomes 𝑓: 0.56 (158223 hom.)
• Consequence: PEX7 ENST00000541292.6 5_prime_UTR, NMD_transcript
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.497

Genes affected

PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one 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 have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX7	NM_000288.4			upstream_gene_variant		ENST00000318471.5
PEX7	XM_006715502.3			upstream_gene_variant
PEX7	XM_047418874.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX7	ENST00000541292.6	c.-95T>C		5_prime_UTR_variant, NMD_transcript_variant	1/11	5
PEX7	ENST00000318471.5			upstream_gene_variant		1	NM_000288.4	P1
PEX7	ENST00000367756.8			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76951 AN: 152078 Hom.: 19989 Cov.: 35

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.511

GnomAD4 exome AF: 0.561 AC: 556246 AN: 992168 Hom.: 158223 Cov.: 13 AF XY: 0.560 AC XY: 282554 AN XY: 504782

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.543

Gnomad4 ASJ exome AF: 0.572

Gnomad4 EAS exome AF: 0.415

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.533

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.531

GnomAD4 genome AF: 0.506 AC: 76974 AN: 152196 Hom.: 19992 Cov.: 35 AF XY: 0.504 AC XY: 37529 AN XY: 74422

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.575

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.517

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.508

Alfa AF: 0.319 Hom.: 671

Bravo AF: 0.502

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Peroxisome biogenesis disorder 9B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.6
Dann	Benign	0.58

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1321471; hg19: chr6-137143709; COSMIC: COSV59248433; COSMIC: COSV59248433;