rs35830695

Variant names:

• chr6-42965726-G-A
• rs35830695
• NM_000287.4:c.2426C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000287.4(PEX6):​c.2426C>T​(p.Ala809Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,613,654 control chromosomes in the GnomAD database, including 3,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (503 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2542 hom.)
• Consequence: PEX6 NM_000287.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 10.0
• Publications: 23 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000287.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.004077047).
• BP6: Variant 6-42965726-G-A is Benign according to our data. Variant chr6-42965726-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 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.2426C>T	p.Ala809Val	missense	Exon 13 of 17	NP_000278.3
	PEX6	NM_001316313.2		c.2162C>T	p.Ala721Val	missense	Exon 13 of 17	NP_001303242.1	Q13608-3
	PEX6	NR_133009.2		n.2210C>T		non_coding_transcript_exon	Exon 11 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	ENST00000304611.13	TSL:1 MANE Select	c.2426C>T	p.Ala809Val	missense	Exon 13 of 17	ENSP00000303511.8	Q13608-1
	PEX6	ENST00000244546.4	TSL:1	c.2179C>T	p.Pro727Ser	missense	Exon 11 of 15	ENSP00000244546.4	Q13608-2
	PEX6	ENST00000858656.1		c.2465C>T	p.Ala822Val	missense	Exon 13 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10919 AN: 152008 Hom.: 503 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.0598

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0655

GnomAD2 exomes AF: 0.0553 AC: 13904 AN: 251470 AF XY: 0.0546

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0450

Gnomad EAS exome AF: 0.0670

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0536

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0558 AC: 81539 AN: 1461528 Hom.: 2542 Cov.: 33 AF XY: 0.0557 AC XY: 40500 AN XY: 727084

African (AFR) AF: 0.131 AC: 4387 AN: 33456

American (AMR) AF: 0.0346 AC: 1547 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 1159 AN: 26130

East Asian (EAS) AF: 0.0639 AC: 2535 AN: 39696

South Asian (SAS) AF: 0.0611 AC: 5266 AN: 86254

European-Finnish (FIN) AF: 0.0350 AC: 1872 AN: 53414

Middle Eastern (MID) AF: 0.0792 AC: 457 AN: 5768

European-Non Finnish (NFE) AF: 0.0547 AC: 60763 AN: 1111702

Other (OTH) AF: 0.0588 AC: 3553 AN: 60384

GnomAD4 genome AF: 0.0718 AC: 10928 AN: 152126 Hom.: 503 Cov.: 32 AF XY: 0.0692 AC XY: 5150 AN XY: 74376

African (AFR) AF: 0.130 AC: 5394 AN: 41458

American (AMR) AF: 0.0406 AC: 621 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3470

East Asian (EAS) AF: 0.0553 AC: 286 AN: 5170

South Asian (SAS) AF: 0.0590 AC: 284 AN: 4816

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10602

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0533 AC: 3627 AN: 67996

Other (OTH) AF: 0.0653 AC: 138 AN: 2114

Alfa AF: 0.0595 Hom.: 1070

Bravo AF: 0.0758

TwinsUK AF: 0.0510 AC: 189

ALSPAC AF: 0.0545 AC: 210

ESP6500AA AF: 0.133 AC: 585

ESP6500EA AF: 0.0535 AC: 460

ExAC AF: 0.0582 AC: 7069

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.0550

EpiControl AF: 0.0530

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	3	Peroxisome biogenesis disorder 4A (Zellweger) (3)
-	-	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	Pathogenic	0.77
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0041	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.34	N
PhyloP100		10
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.86
MPC		0.63
ClinPred		0.040	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.81
Mutation Taster		=8/92	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35830695; hg19: chr6-42933464; COSMIC: COSV55102348; COSMIC: COSV55102348;