ENST00000244546.4:c.2117G>A

Variant names:

• chr6-42965788-C-T
• rs2274515
• ENST00000244546.4:c.2117G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000244546.4(PEX6):​c.2117G>A​(p.Cys706Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,612,834 control chromosomes in the GnomAD database, including 4,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C706F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.066 (564 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4085 hom.)
• Consequence: PEX6 ENST00000244546.4 missense, splice_region
• Scores: Splicing: ADA: 0.002506
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.32
• Publications: 16 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 (MetaRNN=0.0014739037).
• BP6: Variant 6-42965788-C-T is Benign according to our data. Variant chr6-42965788-C-T is described in ClinVar as Benign. ClinVar VariationId is 92785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000244546.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	NM_000287.4	MANE Select	c.2364G>A	p.Val788Val	splice_region synonymous	Exon 13 of 17	NP_000278.3
	PEX6	NM_001316313.2		c.2100G>A	p.Val700Val	splice_region synonymous	Exon 13 of 17	NP_001303242.1
	PEX6	NR_133009.2		n.2148G>A		splice_region non_coding_transcript_exon	Exon 11 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	ENST00000244546.4	TSL:1	c.2117G>A	p.Cys706Tyr	missense splice_region	Exon 11 of 15	ENSP00000244546.4
	PEX6	ENST00000304611.13	TSL:1 MANE Select	c.2364G>A	p.Val788Val	splice_region synonymous	Exon 13 of 17	ENSP00000303511.8
	PEX6	ENST00000858656.1		c.2403G>A	p.Val801Val	synonymous	Exon 13 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 10041 AN: 152066 Hom.: 559 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0579

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0901 AC: 22604 AN: 250900 AF XY: 0.0865

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.0450

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0789

GnomAD4 exome AF: 0.0617 AC: 90120 AN: 1460650 Hom.: 4085 Cov.: 33 AF XY: 0.0629 AC XY: 45724 AN XY: 726690

African (AFR) AF: 0.0552 AC: 1848 AN: 33452

American (AMR) AF: 0.205 AC: 9165 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 1290 AN: 26126

East Asian (EAS) AF: 0.154 AC: 6121 AN: 39678

South Asian (SAS) AF: 0.130 AC: 11177 AN: 86198

European-Finnish (FIN) AF: 0.0584 AC: 3118 AN: 53352

Middle Eastern (MID) AF: 0.0506 AC: 292 AN: 5768

European-Non Finnish (NFE) AF: 0.0476 AC: 52868 AN: 1111010

Other (OTH) AF: 0.0703 AC: 4241 AN: 60348

GnomAD4 genome AF: 0.0661 AC: 10052 AN: 152184 Hom.: 564 Cov.: 32 AF XY: 0.0696 AC XY: 5178 AN XY: 74406

African (AFR) AF: 0.0530 AC: 2202 AN: 41534

American (AMR) AF: 0.151 AC: 2308 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.152 AC: 784 AN: 5158

South Asian (SAS) AF: 0.149 AC: 718 AN: 4812

European-Finnish (FIN) AF: 0.0579 AC: 613 AN: 10596

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3073 AN: 68010

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0556 Hom.: 1445

Bravo AF: 0.0722

TwinsUK AF: 0.0458 AC: 170

ALSPAC AF: 0.0524 AC: 202

ESP6500AA AF: 0.0567 AC: 250

ESP6500EA AF: 0.0447 AC: 384

ExAC AF: 0.0860 AC: 10436

Asia WGS AF: 0.184 AC: 638 AN: 3478

EpiCase AF: 0.0447

EpiControl AF: 0.0444

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Peroxisome biogenesis disorder 4A (Zellweger) (2)
-	-	1	Heimler syndrome 2 (1)
-	-	1	Peroxisome biogenesis disorder (1)
-	-	1	Peroxisome biogenesis disorder 4B (1)
-	-	1	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0015	T
MetaSVM	Uncertain	0.42	D
PhyloP100		1.3
PROVEAN	Benign	0.30	N
REVEL	Benign	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Vest4		0.13
ClinPred		0.0080	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=53/47	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.010		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: rs2274515; hg19: chr6-42933526; COSMIC: COSV55102634; COSMIC: COSV55102634;