Genetic Variant NM_000287.4:c.1802G>A (chr6-42967450-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3PM5PP3PP5BP4

The NM_000287.4(PEX6):c.1802G>A(p.Arg601Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,612,580 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000916141: Transfection of the p.Arg601Gln variant into primary skin fibroblasts cells completely deficient in PEX1 and PEX6 demonstrated that the variant rescued peroxisomal biogenesis in between 35 to 40% of cells indicating a significant residual activity (Ratbi et al. 2015)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R601W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0031 ( 16 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17U:9B:2

Conservation

PhyloP100: 6.99

Publications

32 publications found

Variant links:

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

PEX6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000916141: Transfection of the p.Arg601Gln variant into primary skin fibroblasts cells completely deficient in PEX1 and PEX6 demonstrated that the variant rescued peroxisomal biogenesis in between 35 to 40% of cells indicating a significant residual activity (Ratbi et al. 2015).; SCV001443749: Functional studies of this variant demonstrate that it has significant residual activity, suggesting that it may be a hypomorphic allele (PMID: 26387595).

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-42967451-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 632484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 6-42967450-C-T is Pathogenic according to our data. Variant chr6-42967450-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198709.

BP4

Computational evidence support a benign effect (MetaRNN=0.11544728). . Strength limited to SUPPORTING due to the PP5.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX6	NM_000287.4	MANE Select	c.1802G>A	p.Arg601Gln	missense	Exon 8 of 17	NP_000278.3
PEX6	NM_001316313.2		c.1538G>A	p.Arg513Gln	missense	Exon 8 of 17	NP_001303242.1	Q13608-3
PEX6	NR_133009.2		n.1833G>A		non_coding_transcript_exon	Exon 8 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX6	ENST00000304611.13	TSL:1 MANE Select	c.1802G>A	p.Arg601Gln	missense	Exon 8 of 17	ENSP00000303511.8	Q13608-1
PEX6	ENST00000244546.4	TSL:1	c.1802G>A	p.Arg601Gln	missense	Exon 8 of 15	ENSP00000244546.4	Q13608-2
PEX6	ENST00000858656.1		c.1802G>A	p.Arg601Gln	missense	Exon 8 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00517

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00275

AC:

677

AN:

246348

AF XY:

0.00294

show subpopulations

Gnomad AFR exome

AF:

0.000633

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00423

Gnomad OTH exome

AF:

0.00249

GnomAD4 exome

AF:

0.00312

AC:

4554

AN:

1460302

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

2314

AN XY:

726306

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33472

American (AMR)

AF:

0.00132

AC:

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.000959

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00281

AC:

241

AN:

85820

European-Finnish (FIN)

AF:

0.00173

AC:

AN:

53076

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00356

AC:

3954

AN:

1111550

Other (OTH)

AF:

0.00273

AC:

165

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

267

534

801

1068

1335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00281

AC:

428

AN:

152278

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

189

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41566

American (AMR)

AF:

0.000458

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00517

AC:

352

AN:

68024

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00394

Hom.:

Bravo

AF:

0.00225

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00268

AC:

326

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2 (5)

Heimler syndrome 2 (3)

not specified (3)

Peroxisome biogenesis disorder 4A (Zellweger) (3)

Peroxisome biogenesis disorder 4B (2)

PEX6-related disorder (2)

Peroxisome biogenesis disorder (1)

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.12

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.3

PhyloP100

7.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.94

MPC

0.66

ClinPred

0.083

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.94

Mutation Taster

=41/59

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over