rs61752141

chr6-42978916-C-Gchr6-42978916-C-T

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.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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (50 hom., cov: 33)
  • Exomes 𝑓: 0.029 (645 hom.)
• Consequence: PEX6 NM_000287.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.535

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=0.0027239919).
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4	c.235G>C	p.Ala79Pro	missense_variant	1/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.235G>C	p.Ala79Pro	missense_variant	1/17	1	NM_000287.4	P1
PEX6	ENST00000244546.4	c.235G>C	p.Ala79Pro	missense_variant	1/15	1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3256 AN: 152106 Hom.: 50 Cov.: 33

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.: 44 AF XY: 0.0250 AC XY: 1245 AN XY: 49894

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.: 35 AF XY: 0.0288 AC XY: 18937 AN XY: 657942

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.: 50 Cov.: 33 AF XY: 0.0201 AC XY: 1498 AN XY: 74426

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.: 14

Bravo AF: 0.0205

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0371 AC: 143

ExAC AF: 0.0159 AC: 282

Asia WGS AF: 0.00494 AC: 18 AN: 3452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	- -

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. -

Peroxisome biogenesis disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.57	N;N
PrimateAI	Pathogenic	0.93	D
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	T
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

Other links and lift over

dbSNP: rs61752141; hg19: chr6-42946654;