rs121907889

Variant names:

• chr6-42963149-C-A
• rs121907889
• NM_018960.6:c.529C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_018960.6(GNMT):​c.529C>A​(p.His177Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000762 in 1,611,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H177R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: GNMT NM_018960.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.50
• Publications: 8 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]

CNPY3-GNMT (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

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.529C>A	p.His177Asn	missense	Exon 4 of 6	NP_061833.1	Q14749
	GNMT	NM_001318865.2		c.472C>A	p.His158Asn	missense	Exon 4 of 6	NP_001305794.1	A0A0S2Z5F2
	CNPY3-GNMT	NM_001318857.2		c.346C>A	p.His116Asn	missense	Exon 3 of 5	NP_001305786.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000372808.4	TSL:1 MANE Select	c.529C>A	p.His177Asn	missense	Exon 4 of 6	ENSP00000361894.3	Q14749
	GNMT	ENST00000858688.1		c.520C>A	p.His174Asn	missense	Exon 4 of 6	ENSP00000528747.1
	GNMT	ENST00000858686.1		c.472C>A	p.His158Asn	missense	Exon 4 of 6	ENSP00000528745.1

Frequencies

GnomAD3 genomes AF: 0.000371 AC: 56 AN: 151110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000385

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000604

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000407 AC: 102 AN: 250724 AF XY: 0.000405

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000468

Gnomad NFE exome AF: 0.000679

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000803 AC: 1173 AN: 1460712 Hom.: 1 Cov.: 34 AF XY: 0.000797 AC XY: 579 AN XY: 726680

African (AFR) AF: 0.000209 AC: 7 AN: 33456

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86216

European-Finnish (FIN) AF: 0.000264 AC: 14 AN: 53008

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5278

European-Non Finnish (NFE) AF: 0.000999 AC: 1111 AN: 1111874

Other (OTH) AF: 0.000381 AC: 23 AN: 60324

GnomAD4 genome AF: 0.000371 AC: 56 AN: 151110 Hom.: 0 Cov.: 31 AF XY: 0.000380 AC XY: 28 AN XY: 73672

African (AFR) AF: 0.000195 AC: 8 AN: 41036

American (AMR) AF: 0.000199 AC: 3 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.000385 AC: 4 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000604 AC: 41 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.000397

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Glycine N-methyltransferase deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.68
MPC		0.56
ClinPred		0.30	T
GERP RS		5.7
Varity_R		0.91
gMVP		0.80
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs121907889; hg19: chr6-42930887;