6-42963889-GTTTA-G

Variant names:

• chr6-42963889-GTTTA-G
• rs144286892
• NM_000287.4:c.*442_*445delTAAA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000287.4(PEX6):​c.*442_*445delTAAA 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
• Publications: 9 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]

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]

GNMT Gene-Disease associations (from GenCC):

• glycine N-methyltransferase deficiency

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

CNPY3-GNMT (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 356786.
• 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 rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.*442_*445delTAAA		3_prime_UTR_variant	Exon 17 of 17	ENST00000304611.13	NP_000278.3
GNMT	NM_018960.6	c.*184_*187delTTTA		downstream_gene_variant		ENST00000372808.4	NP_061833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.*442_*445delTAAA		3_prime_UTR_variant	Exon 17 of 17	1	NM_000287.4	ENSP00000303511.8
GNMT	ENST00000372808.4	c.*184_*187delTTTA		downstream_gene_variant		1	NM_018960.6	ENSP00000361894.3

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

African (AFR) AF: 0.918 AC: 13829 AN: 15058

American (AMR) AF: 0.547 AC: 17667 AN: 32278

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 8706 AN: 17236

East Asian (EAS) AF: 0.360 AC: 11246 AN: 31250

South Asian (SAS) AF: 0.645 AC: 35666 AN: 55298

European-Finnish (FIN) AF: 0.501 AC: 15589 AN: 31146

Middle Eastern (MID) AF: 0.617 AC: 1405 AN: 2278

European-Non Finnish (NFE) AF: 0.576 AC: 173204 AN: 300662

Other (OTH) AF: 0.593 AC: 17039 AN: 28744

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

African (AFR) AF: 0.916 AC: 36487 AN: 39824

American (AMR) AF: 0.583 AC: 8603 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1752 AN: 3444

East Asian (EAS) AF: 0.323 AC: 1610 AN: 4978

South Asian (SAS) AF: 0.638 AC: 3006 AN: 4708

European-Finnish (FIN) AF: 0.506 AC: 4943 AN: 9766

Middle Eastern (MID) AF: 0.581 AC: 165 AN: 284

European-Non Finnish (NFE) AF: 0.580 AC: 39107 AN: 67472

Other (OTH) AF: 0.646 AC: 1325 AN: 2050

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:2

Jan 13, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29220678) -

not specified Benign:1

Aug 08, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PEX6 POLYMORPHISM Benign:1

Sep 29, 2023

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Peroxisome biogenesis disorder 1A (Zellweger) Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs144286892; hg19: chr6-42931627;