6-42963928-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000287.4(PEX6):c.*407T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.35 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX6 NM_000287.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00200

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]

GNMT (HGNC:4415): (glycine N-methyltransferase) The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

CNPY3-GNMT (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4	c.*407T>G		3_prime_UTR_variant	17/17	ENST00000304611.13
GNMT	NM_018960.6			downstream_gene_variant		ENST00000372808.4
CNPY3-GNMT	NR_134890.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13	c.*407T>G		3_prime_UTR_variant	17/17	1	NM_000287.4	P1
GNMT	ENST00000372808.4			downstream_gene_variant		1	NM_018960.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 23159 AN: 66232 Hom.: 0 Cov.: 12 FAILED QC

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.342

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000396 AC: 116 AN: 292646 Hom.: 0 Cov.: 3 AF XY: 0.000361 AC XY: 57 AN XY: 157796

Gnomad4 AFR exome AF: 0.000108

Gnomad4 AMR exome AF: 0.000516

Gnomad4 ASJ exome AF: 0.000225

Gnomad4 EAS exome AF: 0.000452

Gnomad4 SAS exome AF: 0.000338

Gnomad4 FIN exome AF: 0.000280

Gnomad4 NFE exome AF: 0.000431

Gnomad4 OTH exome AF: 0.000389

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.349 AC: 23157 AN: 66266 Hom.: 0 Cov.: 12 AF XY: 0.330 AC XY: 10335 AN XY: 31348

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.339

Alfa AF: 0.158 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 4A (Zellweger) Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.5
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886061409; hg19: chr6-42931666;