6-42978870-G-T

Variant names:

• chr6-42978870-G-T
• rs61752143
• NM_000287.4:c.281C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A94P) has been classified as Likely pathogenic.

• 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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000287.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42978871-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3240098.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4187603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.281C>A	p.Ala94Glu	missense_variant	Exon 1 of 17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.281C>A	p.Ala94Glu	missense_variant	Exon 1 of 17	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4	c.281C>A	p.Ala94Glu	missense_variant	Exon 1 of 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

African (AFR) AF: 0.00 AC: 0 AN: 27102

American (AMR) AF: 0.00 AC: 0 AN: 28950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23276

East Asian (EAS) AF: 0.00 AC: 0 AN: 31428

South Asian (SAS) AF: 0.00 AC: 0 AN: 74386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3918

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062520

Other (OTH) AF: 0.00 AC: 0 AN: 55712

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

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is also known as Nt281C>A (A94K). 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). -

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
PhyloP100		0.60
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
PromoterAI		-0.0050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.73
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs61752143; hg19: chr6-42946608;