rs2274516

Variant names:

• chr6-42965097-C-T
• rs2274516
• NM_000287.4:c.2644G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.61

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]

ACMG classification

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 rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.2644G>A	p.Val882Ile	missense_variant	Exon 15 of 17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.2644G>A	p.Val882Ile	missense_variant	Exon 15 of 17	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546	c.*180G>A		3_prime_UTR_variant	Exon 13 of 15	1		ENSP00000244546.4

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3202 AN: 152192 Hom.: 43 Cov.: 32

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.: 96 AF XY: 0.0234 AC XY: 3175 AN XY: 135908

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.: 34 AF XY: 0.0264 AC XY: 19178 AN XY: 727216

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.: 43 Cov.: 32 AF XY: 0.0221 AC XY: 1648 AN XY: 74462

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.: 95

Bravo AF: 0.0179

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0277 AC: 238

ExAC AF: 0.0220 AC: 2665

Asia WGS AF: 0.0230 AC: 79 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

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

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. -

Zellweger spectrum disorders Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder Benign:1

Feb 04, 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	0.095
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.0
DANN	Benign	0.83
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.77	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.29
Sift	Benign	1.0	T
Sift4G	Benign	0.63	T
Polyphen		0.46	P
Vest4		0.060
MPC		0.12
ClinPred		0.0090	T
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

Other links and lift over

dbSNP: rs2274516; hg19: chr6-42932835;