NM_018960.6:c.167A>G

Variant names:

• chr6-42960934-A-G
• rs1300530729
• NM_018960.6:c.167A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018960.6(GNMT):​c.167A>G​(p.His56Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GNMT NM_018960.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.57
• Publications: 0 publications found

Genes affected

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]

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]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CNPY3-GNMT (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21426094).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018960.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	NM_018960.6	MANE Select	c.167A>G	p.His56Arg	missense	Exon 1 of 6	NP_061833.1	Q14749
	GNMT	NM_001318865.2		c.167A>G	p.His56Arg	missense	Exon 1 of 6	NP_001305794.1	A0A0S2Z5F2
	CNPY3-GNMT	NM_001318857.2		c.152-1828A>G		intron	N/A	NP_001305786.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000372808.4	TSL:1 MANE Select	c.167A>G	p.His56Arg	missense	Exon 1 of 6	ENSP00000361894.3	Q14749
	GNMT	ENST00000858688.1		c.167A>G	p.His56Arg	missense	Exon 1 of 6	ENSP00000528747.1
	GNMT	ENST00000858686.1		c.167A>G	p.His56Arg	missense	Exon 1 of 6	ENSP00000528745.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000603 AC: 1 AN: 165800 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412530 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 699336

African (AFR) AF: 0.00 AC: 0 AN: 32578

American (AMR) AF: 0.0000260 AC: 1 AN: 38432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37520

South Asian (SAS) AF: 0.00 AC: 0 AN: 81018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092462

Other (OTH) AF: 0.00 AC: 0 AN: 58670

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0097	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.00030
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PhyloP100		8.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.54	T
Sift4G	Benign	0.80	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.54		Gain of MoRF binding (P = 0.0104)
MVP		0.65
MPC		1.3
ClinPred		0.31	T
GERP RS		3.4
PromoterAI		0.012	Neutral
Varity_R		0.33
gMVP		0.66
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1300530729; hg19: chr6-42928672;