dbSNP rs121907888: GNMT:p.Leu50His (chr6-42960916-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_018960.6(GNMT):c.149T>A(p.Leu50His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,411,522 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L50P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GNMT
NM_018960.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.47

Publications

0 publications found

Variant links:

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]

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

GNMT links:

CNPY3-GNMT (HGNC:):

CNPY3-GNMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-42960916-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4169.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNMT	NM_018960.6	MANE Select	c.149T>A	p.Leu50His	missense	Exon 1 of 6	NP_061833.1
GNMT	NM_001318865.2		c.149T>A	p.Leu50His	missense	Exon 1 of 6	NP_001305794.1
GNMT	NR_134899.2		n.163T>A		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000372808.4	TSL:1 MANE Select	c.149T>A	p.Leu50His	missense	Exon 1 of 6	ENSP00000361894.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1411522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698530

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32538

American (AMR)

AF:

0.00

AC:

AN:

37980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25348

East Asian (EAS)

AF:

0.00

AC:

AN:

37340

South Asian (SAS)

AF:

0.00

AC:

AN:

80774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42472

Middle Eastern (MID)

AF:

0.000185

AC:

AN:

5394

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091006

Other (OTH)

AF:

0.00

AC:

AN:

58670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.90

PhyloP100

3.5

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.51

MutPred

0.59

Gain of catalytic residue at L52 (P = 0.0626)

MVP

0.66

MPC

2.2

ClinPred

0.98

GERP RS

4.8

PromoterAI

-0.071

Neutral

(source)

Varity_R

0.67

gMVP

0.81

Mutation Taster

=38/62

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over