rs2274517

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0300

Publications

35 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: Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_000287.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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

Gene	Transcript	Tags	HGVSc	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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.522

AC XY:

379545

AN XY:

727052

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

23020

46041

69061

92082

115102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16840

33680

50520

67360

84200

<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:

0.565

AC:

85933

AN:

152040

Hom.:

25697

Cov.:

AF XY:

0.556

AC XY:

41325

AN XY:

74306

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1805

3610

5416

7221

9026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

726

1452

2178

2904

3630

<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:

0.573

Hom.:

15072

Bravo

AF:

0.569

Asia WGS

AF:

0.355

AC:

1237

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Heimler syndrome 2 (1)

not provided (1)

Peroxisome biogenesis disorder 4A (Zellweger) (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

(source)

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)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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