rs2274517

Positions:

• chr6-42964977-C-T

Variant summary

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

The NM_000287.4(PEX6):​c.2667-48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,506 control chromosomes in the GnomAD database, including 229,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25697 hom., cov: 32)
  • Exomes 𝑓: 0.52 (203443 hom.)
• Consequence: PEX6 NM_000287.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0300

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-42964977-C-T is Benign according to our data. Variant chr6-42964977-C-T is described in ClinVar as [Benign]. Clinvar id is 1181155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4	c.2667-48G>A		intron_variant		ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.2667-48G>A		intron_variant		1	NM_000287.4	P1
PEX6	ENST00000244546.4	c.*203-48G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85844 AN: 151922 Hom.: 25661 Cov.: 32

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.554

GnomAD3 exomes AF: 0.480 AC: 120515 AN: 251274 Hom.: 31265 AF XY: 0.487 AC XY: 66076 AN XY: 135810

Gnomad AFR exome AF: 0.759

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.513

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.531

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.521 AC: 761788 AN: 1461466 Hom.: 203443 Cov.: 41 AF XY: 0.522 AC XY: 379545 AN XY: 727052

Gnomad4 AFR exome AF: 0.759

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.466

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.537

Gnomad4 OTH exome AF: 0.517

GnomAD4 genome AF: 0.565 AC: 85933 AN: 152040 Hom.: 25697 Cov.: 32 AF XY: 0.556 AC XY: 41325 AN XY: 74306

Gnomad4 AFR AF: 0.754

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.550

Alfa AF: 0.534 Hom.: 7314

Bravo AF: 0.569

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 4A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Heimler syndrome 2 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

Aug 07, 2018

- -

Peroxisome biogenesis disorder 4B 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	-0.81
CADD	Benign	1.7
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2274517; hg19: chr6-42932715; COSMIC: COSV55103286; COSMIC: COSV55103286;