6-136822589-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000367756.8(PEX7):c.-77T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,362,798 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (6 hom., cov: 35)
  • Exomes 𝑓: 0.00085 (9 hom.)
• Consequence: PEX7 ENST00000367756.8 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.767

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00188 (287/152334) while in subpopulation EAS AF= 0.0253 (131/5174). AF 95% confidence interval is 0.0218. There are 6 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 6 AR gene

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	ENST00000367756.8	c.-77T>C		5_prime_UTR_variant	1/4	3
PEX7	ENST00000541292.6	c.-77T>C		5_prime_UTR_variant, NMD_transcript_variant	1/11	5
PEX7	ENST00000318471.5			upstream_gene_variant		1	NM_000288.4	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152216 Hom.: 6 Cov.: 35

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000848 AC: 1026 AN: 1210464 Hom.: 9 Cov.: 17 AF XY: 0.000877 AC XY: 530 AN XY: 604606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00352

Gnomad4 ASJ exome AF: 0.0000430

Gnomad4 EAS exome AF: 0.0132

Gnomad4 SAS exome AF: 0.000461

Gnomad4 FIN exome AF: 0.00685

Gnomad4 NFE exome AF: 0.0000862

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152334 Hom.: 6 Cov.: 35 AF XY: 0.00221 AC XY: 165 AN XY: 74498

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0253

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.00168

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Phytanic acid storage disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Rhizomelic chondrodysplasia punctata Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.4
Dann	Benign	0.61

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: rs1321472; hg19: chr6-137143727;