dbSNP rs1129186: PEX6:p.Glu938Glu (chr6-42964464-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000287.4(PEX6):c.2814G>A(p.Glu938Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,612,222 control chromosomes in the GnomAD database, including 227,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24877 hom., cov: 33)

Exomes 𝑓: 0.52 ( 202631 hom. )

Consequence

PEX6
NM_000287.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.520

Publications

31 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 6-42964464-C-T is Benign according to our data. Variant chr6-42964464-C-T is described in ClinVar as Benign. ClinVar VariationId is 92786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.52 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.725 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	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX6	NM_000287.4	MANE Select	c.2814G>A	p.Glu938Glu	synonymous	Exon 17 of 17	NP_000278.3
PEX6	NM_001316313.2		c.2550G>A	p.Glu850Glu	synonymous	Exon 17 of 17	NP_001303242.1	Q13608-3
PEX6	NR_133009.2		n.2598G>A		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX6	ENST00000304611.13	TSL:1 MANE Select	c.2814G>A	p.Glu938Glu	synonymous	Exon 17 of 17	ENSP00000303511.8	Q13608-1
PEX6	ENST00000244546.4	TSL:1	c.*350G>A		3_prime_UTR	Exon 15 of 15	ENSP00000244546.4	Q13608-2
PEX6	ENST00000858656.1		c.2853G>A	p.Glu951Glu	synonymous	Exon 17 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes

AF:

0.558

AC:

84663

AN:

151794

Hom.:

24839

Cov.:

show subpopulations

Gnomad AFR

AF:

0.732

Gnomad AMI

AF:

0.671

Gnomad AMR

AF:

0.419

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.462

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.535

Gnomad OTH

AF:

0.551

GnomAD2 exomes

AF:

0.476

AC:

118313

AN:

248410

AF XY:

0.484

show subpopulations

Gnomad AFR exome

AF:

0.735

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.468

Gnomad EAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.456

Gnomad NFE exome

AF:

0.530

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.520

AC:

760079

AN:

1460310

Hom.:

202631

Cov.:

AF XY:

0.521

AC XY:

378761

AN XY:

726500

show subpopulations

African (AFR)

AF:

0.738

AC:

24690

AN:

33454

American (AMR)

AF:

0.330

AC:

14774

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.466

AC:

12173

AN:

26134

East Asian (EAS)

AF:

0.205

AC:

8135

AN:

39694

South Asian (SAS)

AF:

0.522

AC:

44957

AN:

86204

European-Finnish (FIN)

AF:

0.454

AC:

24125

AN:

53106

Middle Eastern (MID)

AF:

0.570

AC:

3089

AN:

5422

European-Non Finnish (NFE)

AF:

0.537

AC:

597049

AN:

1111274

Other (OTH)

AF:

0.515

AC:

31087

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

19398

38795

58193

77590

96988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16820

33640

50460

67280

84100

<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:

0.558

AC:

84754

AN:

151912

Hom.:

24877

Cov.:

AF XY:

0.549

AC XY:

40736

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.732

AC:

30372

AN:

41472

American (AMR)

AF:

0.418

AC:

6398

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

1615

AN:

3472

East Asian (EAS)

AF:

0.182

AC:

941

AN:

5174

South Asian (SAS)

AF:

0.491

AC:

2357

AN:

4802

European-Finnish (FIN)

AF:

0.462

AC:

4865

AN:

10520

Middle Eastern (MID)

AF:

0.503

AC:

148

AN:

294

European-Non Finnish (NFE)

AF:

0.535

AC:

36295

AN:

67874

Other (OTH)

AF:

0.547

AC:

1156

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1844

3689

5533

7378

9222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<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:

0.550

Hom.:

11833

Bravo

AF:

0.562

Asia WGS

AF:

0.353

AC:

1231

AN:

3478

EpiCase

AF:

0.539

EpiControl

AF:

0.537

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Peroxisome biogenesis disorder 4A (Zellweger) (2)

Heimler syndrome 2 (1)

Peroxisome biogenesis disorder (1)

Peroxisome biogenesis disorder 4B (1)

Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

6.3

(source)

DANN

Benign

0.77

PhyloP100

0.52

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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