6-42978916-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000287.4(PEX6):c.235G>A(p.Ala79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,486,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.535

Publications

5 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_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013773143).

BP6

Variant 6-42978916-C-T is Benign according to our data. Variant chr6-42978916-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 794739.

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.235G>A	p.Ala79Thr	missense	Exon 1 of 17	NP_000278.3
PEX6	NM_001316313.2		c.235G>A	p.Ala79Thr	missense	Exon 1 of 17	NP_001303242.1	Q13608-3
PEX6	NR_133009.2		n.266G>A		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX6	ENST00000304611.13	TSL:1 MANE Select	c.235G>A	p.Ala79Thr	missense	Exon 1 of 17	ENSP00000303511.8	Q13608-1
PEX6	ENST00000244546.4	TSL:1	c.235G>A	p.Ala79Thr	missense	Exon 1 of 15	ENSP00000244546.4	Q13608-2
PEX6	ENST00000858656.1		c.235G>A	p.Ala79Thr	missense	Exon 1 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00434

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000445

AC:

AN:

87674

AF XY:

0.000341

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000585

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00582

Gnomad NFE exome

AF:

0.0000913

Gnomad OTH exome

AF:

0.00153

GnomAD4 exome

AF:

0.000208

AC:

278

AN:

1334268

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

122

AN XY:

657966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26910

American (AMR)

AF:

0.0000352

AC:

AN:

28416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23376

East Asian (EAS)

AF:

0.00

AC:

AN:

30408

South Asian (SAS)

AF:

0.00

AC:

AN:

73810

European-Finnish (FIN)

AF:

0.00588

AC:

196

AN:

33338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3924

European-Non Finnish (NFE)

AF:

0.0000661

AC:

AN:

1058736

Other (OTH)

AF:

0.000199

AC:

AN:

55350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000388

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00434

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.000159

Hom.:

Bravo

AF:

0.0000831

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Peroxisome biogenesis disorder (1)

Peroxisome biogenesis disorder 4A (Zellweger) (1)

PEX6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.69

PhyloP100

0.54

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.34

REVEL

Benign

0.14

Sift

Benign

0.21

Sift4G

Benign

0.74

Polyphen

0.0080

Vest4

0.15

MutPred

0.25

Gain of phosphorylation at A79 (P = 0.0556)

MVP

0.82

MPC

1.7

ClinPred

0.095

GERP RS

3.0

PromoterAI

-0.077

Neutral

(source)

Varity_R

0.090

gMVP

0.45

Mutation Taster

=96/4

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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