6-42960916-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_018960.6(GNMT):c.149T>C(p.Leu50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,411,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

GNMT
NM_018960.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.47

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 6-42960916-T-C is Pathogenic according to our data. 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>C	p.Leu50Pro	missense	Exon 1 of 6	NP_061833.1
GNMT	NM_001318865.2		c.149T>C	p.Leu50Pro	missense	Exon 1 of 6	NP_001305794.1
GNMT	NR_134899.2		n.163T>C		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>C	p.Leu50Pro	missense	Exon 1 of 6	ENSP00000361894.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000183

AC:

AN:

164362

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000232

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000354

AC:

AN:

1411522

Hom.:

Cov.:

AF XY:

0.00000429

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:

0.000107

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:

0.00

AC:

AN:

5394

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091006

Other (OTH)

AF:

0.0000170

AC:

AN:

58670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000174

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Glycine N-methyltransferase deficiency

Pathogenic:1

Jan 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.90

PhyloP100

3.5

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.63

Sift

Uncertain

0.014

Sift4G

Uncertain

0.033

Polyphen

1.0

Vest4

0.78

MutPred

0.89

Loss of stability (P = 0.0631)

MVP

0.92

MPC

2.6

ClinPred

0.85

GERP RS

4.8

PromoterAI

0.027

Neutral

(source)

Varity_R

0.91

gMVP

0.96

Mutation Taster

=7/93

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over