rs1051218

Variant names:

• chr6-42964123-G-A
• rs1051218
• NM_000287.4:c.*212C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000287.4(PEX6):​c.*212C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 612,356 control chromosomes in the GnomAD database, including 331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (60 hom., cov: 32)
  • Exomes 𝑓: 0.029 (271 hom.)
• Consequence: PEX6 NM_000287.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.113
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-42964123-G-A is Benign according to our data. Variant chr6-42964123-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 356790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3484/152336) while in subpopulation NFE AF = 0.0337 (2290/68034). AF 95% confidence interval is 0.0325. There are 60 homozygotes in GnomAd4. There are 1626 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.*212C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000304611.13	NP_000278.3
GNMT	NM_018960.6	c.*417G>A		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.*212C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_000287.4	ENSP00000303511.8
GNMT	ENST00000372808.4	c.*417G>A		downstream_gene_variant		1	NM_018960.6	ENSP00000361894.3
PEX6	ENST00000244546.4	c.*691C>T		downstream_gene_variant		1		ENSP00000244546.4

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3485 AN: 152218 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0901

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0293 AC: 13460 AN: 460020 Hom.: 271 Cov.: 5 AF XY: 0.0292 AC XY: 7069 AN XY: 242422

African (AFR) AF: 0.00534 AC: 68 AN: 12728

American (AMR) AF: 0.0148 AC: 291 AN: 19682

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 1336 AN: 13808

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30860

South Asian (SAS) AF: 0.0254 AC: 1175 AN: 46314

European-Finnish (FIN) AF: 0.0234 AC: 694 AN: 29630

Middle Eastern (MID) AF: 0.0256 AC: 51 AN: 1990

European-Non Finnish (NFE) AF: 0.0324 AC: 9031 AN: 278766

Other (OTH) AF: 0.0310 AC: 813 AN: 26242

GnomAD4 genome AF: 0.0229 AC: 3484 AN: 152336 Hom.: 60 Cov.: 32 AF XY: 0.0218 AC XY: 1626 AN XY: 74486

African (AFR) AF: 0.00544 AC: 226 AN: 41578

American (AMR) AF: 0.0163 AC: 249 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0901 AC: 313 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0190 AC: 92 AN: 4832

European-Finnish (FIN) AF: 0.0217 AC: 230 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2290 AN: 68034

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0279 Hom.: 10

Bravo AF: 0.0220

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Peroxisome biogenesis disorder 4A (Zellweger) Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.3
DANN	Benign	0.41
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1051218; hg19: chr6-42931861;