rs2274517

Variant names:

• chr6-42964977-C-T
• rs2274517
• NM_000287.4:c.2667-48G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 35 publications found

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]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000287.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	NM_000287.4	MANE Select	c.2667-48G>A		intron	N/A	NP_000278.3
	PEX6	NM_001316313.2		c.2403-48G>A		intron	N/A	NP_001303242.1	Q13608-3
	PEX6	NR_133009.2		n.2451-48G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	ENST00000304611.13	TSL:1 MANE Select	c.2667-48G>A		intron	N/A	ENSP00000303511.8	Q13608-1
	PEX6	ENST00000244546.4	TSL:1	c.*203-48G>A		intron	N/A	ENSP00000244546.4	Q13608-2
	PEX6	ENST00000858656.1		c.2706-48G>A		intron	N/A	ENSP00000528715.1

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

GnomAD2 exomes AF: 0.480 AC: 120515 AN: 251274 AF XY: 0.487

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 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

African (AFR) AF: 0.759 AC: 25414 AN: 33476

American (AMR) AF: 0.332 AC: 14868 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 12172 AN: 26132

East Asian (EAS) AF: 0.205 AC: 8152 AN: 39696

South Asian (SAS) AF: 0.522 AC: 44980 AN: 86246

European-Finnish (FIN) AF: 0.454 AC: 24225 AN: 53346

Middle Eastern (MID) AF: 0.569 AC: 3284 AN: 5768

European-Non Finnish (NFE) AF: 0.537 AC: 597468 AN: 1111696

Other (OTH) AF: 0.517 AC: 31225 AN: 60390

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

African (AFR) AF: 0.754 AC: 31292 AN: 41476

American (AMR) AF: 0.423 AC: 6454 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1615 AN: 3472

East Asian (EAS) AF: 0.184 AC: 948 AN: 5164

South Asian (SAS) AF: 0.492 AC: 2372 AN: 4824

European-Finnish (FIN) AF: 0.466 AC: 4916 AN: 10548

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36420 AN: 67980

Other (OTH) AF: 0.550 AC: 1159 AN: 2106

Alfa AF: 0.573 Hom.: 15072

Bravo AF: 0.569

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Heimler syndrome 2 (1)
-	-	1	not provided (1)
-	-	1	Peroxisome biogenesis disorder 4A (Zellweger) (1)
-	-	1	Peroxisome biogenesis disorder 4B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.60
PhyloP100		0.030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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