6-42978870-G-T

Position:

• chr6-42978870-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000287.4(PEX6):​c.281C>A​(p.Ala94Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX6 NM_000287.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.604

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4187603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX6	NM_000287.4	c.281C>A	p.Ala94Glu	missense_variant	1/17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.281C>A	p.Ala94Glu	missense_variant	1/17	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4	c.281C>A	p.Ala94Glu	missense_variant	1/15	1		ENSP00000244546.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1340542 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 661400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ala94 amino acid residue in PEX6. Other variant(s) that disrupt this residue have been observed in individuals with PEX6-related conditions (PMID: 29047053), which suggests that this may be a clinically significant amino acid residue. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1394141). This variant is also known as Nt281C>A (A94K). This missense change has been observed in individual(s) with peroxisome biogenesis disorders in the Zellweger syndrome spectrum (PMID: 15542397). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 94 of the PEX6 protein (p.Ala94Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T;.
Eigen	Benign	-0.0051
Eigen_PC	Benign	0.050
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.39	N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.079	T;D
Polyphen		0.77	P;.
Vest4		0.17
MutPred		0.64		Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);
MVP		0.97
MPC		3.5
ClinPred		0.84	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61752143; hg19: chr6-42946608;