rs144286892

chr6-42963889-GTTTA-Gchr6-42963889-GTTTA-GTTTATTTA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000287.4(PEX6):c.*442_*445del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 662,130 control chromosomes in the GnomAD database, including 121,301 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.66 (34223 hom., cov: 0)
  • Exomes 𝑓: 0.57 (87078 hom.)
• Consequence: PEX6 NM_000287.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.69

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 6-42963889-GTTTA-G is Benign according to our data. Variant chr6-42963889-GTTTA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 356786.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr6-42963889-GTTTA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4	c.*442_*445del		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.*442_*445del		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: 0.658 AC: 97493 AN: 148062 Hom.: 34168 Cov.: 0

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.584

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.573 AC: 294351 AN: 513950 Hom.: 87078 AF XY: 0.577 AC XY: 158414 AN XY: 274648

Gnomad4 AFR exome AF: 0.918

Gnomad4 AMR exome AF: 0.547

Gnomad4 ASJ exome AF: 0.505

Gnomad4 EAS exome AF: 0.360

Gnomad4 SAS exome AF: 0.645

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.576

Gnomad4 OTH exome AF: 0.593

GnomAD4 genome AF: 0.659 AC: 97611 AN: 148180 Hom.: 34223 Cov.: 0 AF XY: 0.651 AC XY: 46855 AN XY: 71946

Gnomad4 AFR AF: 0.916

Gnomad4 AMR AF: 0.583

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.638

Gnomad4 FIN AF: 0.506

Gnomad4 NFE AF: 0.580

Gnomad4 OTH AF: 0.646

Alfa AF: 0.628 Hom.: 3793

Bravo AF: 0.678

Asia WGS AF: 0.542 AC: 1888 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2021	This variant is associated with the following publications: (PMID: 29220678) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 08, 2018

- -

PEX6 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 29, 2023

- -

Peroxisome biogenesis disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2020

- -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144286892; hg19: chr6-42931627;