rs736158

Variant names:

• chr6-42964016-G-A
• rs736158
• NM_000287.4:c.*319C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000287.4(PEX6):​c.*319C>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 0.0691 in 558,780 control chromosomes in the GnomAD database, including 2,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (562 hom., cov: 31)
  • Exomes 𝑓: 0.070 (1492 hom.)
• Consequence: PEX6 NM_000287.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.315
• Publications: 4 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=-0.75).
• BP6: Variant 6-42964016-G-A is Benign according to our data. Variant chr6-42964016-G-A is described in ClinVar as Benign. ClinVar VariationId is 356789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.*319C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000304611.13	NP_000278.3
GNMT	NM_018960.6	c.*310G>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.*319C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_000287.4	ENSP00000303511.8
GNMT	ENST00000372808.4	c.*310G>A		downstream_gene_variant		1	NM_018960.6	ENSP00000361894.3

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 9975 AN: 151404 Hom.: 557 Cov.: 31

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0687

GnomAD4 exome AF: 0.0702 AC: 28599 AN: 407256 Hom.: 1492 Cov.: 3 AF XY: 0.0730 AC XY: 15736 AN XY: 215646

African (AFR) AF: 0.0565 AC: 658 AN: 11636

American (AMR) AF: 0.179 AC: 3125 AN: 17436

Ashkenazi Jewish (ASJ) AF: 0.0492 AC: 607 AN: 12338

East Asian (EAS) AF: 0.150 AC: 4006 AN: 26712

South Asian (SAS) AF: 0.133 AC: 5938 AN: 44722

European-Finnish (FIN) AF: 0.0568 AC: 1393 AN: 24546

Middle Eastern (MID) AF: 0.0506 AC: 90 AN: 1780

European-Non Finnish (NFE) AF: 0.0451 AC: 11030 AN: 244592

Other (OTH) AF: 0.0746 AC: 1752 AN: 23494

GnomAD4 genome AF: 0.0659 AC: 9986 AN: 151524 Hom.: 562 Cov.: 31 AF XY: 0.0693 AC XY: 5127 AN XY: 73982

African (AFR) AF: 0.0529 AC: 2186 AN: 41332

American (AMR) AF: 0.151 AC: 2290 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 158 AN: 3466

East Asian (EAS) AF: 0.152 AC: 773 AN: 5088

South Asian (SAS) AF: 0.148 AC: 711 AN: 4796

European-Finnish (FIN) AF: 0.0576 AC: 603 AN: 10468

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3069 AN: 67862

Other (OTH) AF: 0.0746 AC: 157 AN: 2104

Alfa AF: 0.0631 Hom.: 264

Bravo AF: 0.0722

Asia WGS AF: 0.184 AC: 638 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 4A (Zellweger) Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.2
DANN	Benign	0.56
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs736158; hg19: chr6-42931754;