rs121907889

Positions:

• chr6-42963149-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 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 (★).

• 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

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNMT	NM_018960.6	c.529C>A	p.His177Asn	missense_variant	4/6	ENST00000372808.4	NP_061833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNMT	ENST00000372808.4	c.529C>A	p.His177Asn	missense_variant	4/6	1	NM_018960.6	ENSP00000361894.3

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

GnomAD3 exomes AF: 0.000407 AC: 102 AN: 250724 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135648

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 SAS exome AF: 0.000131

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

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000264

Gnomad4 NFE exome AF: 0.000999

Gnomad4 OTH exome AF: 0.000381

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

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000385

Gnomad4 NFE AF: 0.000604

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000636 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

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycine N-methyltransferase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2002

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2023

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 177 of the GNMT protein (p.His177Asn). This variant is present in population databases (rs121907889, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glycine N-methyltransferase deficiency (PMID: 11810299). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His176Asn. ClinVar contains an entry for this variant (Variation ID: 4170). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNMT protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121907889; hg19: chr6-42930887;