chr6-42978916-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000287.4(PEX6):c.235G>C(p.Ala79Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,486,432 control chromosomes in the GnomAD database, including 695 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 50 hom., cov: 33)

Exomes 𝑓: 0.029 ( 645 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.535

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027239919).

BP6

Variant 6-42978916-C-G is Benign according to our data. Variant chr6-42978916-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 92784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42978916-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3254/152214) while in subpopulation NFE AF= 0.0325 (2210/67982). AF 95% confidence interval is 0.0314. There are 50 homozygotes in gnomad4. There are 1498 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4 link	c.235G>C	p.Ala79Pro	missense_variant	Exon 1 of 17	ENST00000304611.13	NP_000278.3	Q13608-1A0A024RD09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13 link	c.235G>C	p.Ala79Pro	missense_variant	Exon 1 of 17	1	NM_000287.4	ENSP00000303511.8		Q13608-1
PEX6	ENST00000244546.4 link	c.235G>C	p.Ala79Pro	missense_variant	Exon 1 of 15	1		ENSP00000244546.4		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3256

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00541

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0752

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0325

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0246

AC:

2155

AN:

87674

Hom.:

AF XY:

0.0250

AC XY:

1245

AN XY:

49894

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.00948

Gnomad ASJ exome

AF:

0.0793

Gnomad EAS exome

AF:

0.000203

Gnomad SAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0315

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0291

AC:

38786

AN:

1334218

Hom.:

645

Cov.:

AF XY:

0.0288

AC XY:

18937

AN XY:

657942

show subpopulations

Gnomad4 AFR exome

AF:

0.00409

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.0812

Gnomad4 EAS exome

AF:

0.0000987

Gnomad4 SAS exome

AF:

0.0132

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.0312

Gnomad4 OTH exome

AF:

0.0289

GnomAD4 genome

AF:

0.0214

AC:

3254

AN:

152214

Hom.:

Cov.:

AF XY:

0.0201

AC XY:

1498

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00539

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.0752

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00911

Gnomad4 FIN

AF:

0.0218

Gnomad4 NFE

AF:

0.0325

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0183

Hom.:

Bravo

AF:

0.0205

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0371

AC:

143

ExAC

AF:

0.0159

AC:

282

Asia WGS

AF:

0.00494

AC:

AN:

3452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 20, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

May 15, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Peroxisome biogenesis disorder

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.6

L;L

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.38

N;N

REVEL

Benign

0.13

Sift

Benign

0.17

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.0040

B;.

Vest4

0.24

MPC

2.9

ClinPred

0.030

GERP RS

3.0

Varity_R

0.24

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over