rs2274516

Positions:

chr6-42965097-C-T

Variant summary

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

The NM_000287.4(PEX6):c.2644G>A(p.Val882Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,614,138 control chromosomes in the GnomAD database, including 641 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 43 hom., cov: 32)

Exomes 𝑓: 0.026 ( 598 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.61

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=0.009148866).

BP6

Variant 6-42965097-C-T is Benign according to our data. Variant chr6-42965097-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42965097-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.021 (3197/152310) while in subpopulation NFE AF= 0.0274 (1866/68030). AF 95% confidence interval is 0.0264. There are 43 homozygotes in gnomad4. There are 1648 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX6	NM_000287.4 linkuse as main transcript	c.2644G>A	p.Val882Ile	missense_variant	15/17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13 linkuse as main transcript	c.2644G>A	p.Val882Ile	missense_variant	15/17	1	NM_000287.4	ENSP00000303511	P1	Q13608-1
PEX6	ENST00000244546.4 linkuse as main transcript	c.*180G>A		3_prime_UTR_variant	13/15	1		ENSP00000244546		Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3202

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00955

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.0233

Gnomad SAS

AF:

0.0254

Gnomad FIN

AF:

0.0444

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0226

AC:

5690

AN:

251470

Hom.:

AF XY:

0.0234

AC XY:

3175

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00861

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0239

Gnomad SAS exome

AF:

0.0249

Gnomad FIN exome

AF:

0.0403

Gnomad NFE exome

AF:

0.0266

Gnomad OTH exome

AF:

0.0239

GnomAD4 exome

AF:

0.0265

AC:

38684

AN:

1461828

Hom.:

598

Cov.:

AF XY:

0.0264

AC XY:

19178

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00756

Gnomad4 AMR exome

AF:

0.00736

Gnomad4 ASJ exome

AF:

0.00627

Gnomad4 EAS exome

AF:

0.0163

Gnomad4 SAS exome

AF:

0.0251

Gnomad4 FIN exome

AF:

0.0397

Gnomad4 NFE exome

AF:

0.0284

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0210

AC:

3197

AN:

152310

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1648

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00950

Gnomad4 AMR

AF:

0.00778

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.0231

Gnomad4 SAS

AF:

0.0250

Gnomad4 FIN

AF:

0.0444

Gnomad4 NFE

AF:

0.0274

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0260

Hom.:

Bravo

AF:

0.0179

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.0277

AC:

238

ExAC

AF:

0.0220

AC:

2665

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0256

EpiControl

AF:

0.0238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Peroxisome biogenesis disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

9.0

DANN

Benign

0.83

DEOGEN2

Benign

0.073

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.51

MutationAssessor

Benign

-0.77

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

0.11

REVEL

Benign

0.29

Sift

Benign

1.0

Sift4G

Benign

0.63

Polyphen

0.46

Vest4

0.060

MPC

0.12

ClinPred

0.0090

GERP RS

2.6

Varity_R

0.021

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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