rs864321678

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_018960.6(GNMT):ā€‹c.422A>Gā€‹(p.Asn141Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,762 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: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

GNMT
NM_018960.6 missense

Scores

5
6
8

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.46
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 6-42962849-A-G is Pathogenic according to our data. Variant chr6-42962849-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 218931.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GNMTNM_018960.6 linkuse as main transcriptc.422A>G p.Asn141Ser missense_variant 3/6 ENST00000372808.4
CNPY3-GNMTNR_134890.2 linkuse as main transcriptn.427A>G non_coding_transcript_exon_variant 3/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GNMTENST00000372808.4 linkuse as main transcriptc.422A>G p.Asn141Ser missense_variant 3/61 NM_018960.6 P1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461762
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Glycine N-methyltransferase deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2003- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D
Eigen
Uncertain
0.63
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
0.97
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.6
D
REVEL
Uncertain
0.51
Sift
Benign
0.18
T
Sift4G
Benign
0.088
T
Polyphen
1.0
D
Vest4
0.84
MutPred
0.92
Gain of sheet (P = 0.1451);
MVP
0.72
MPC
0.34
ClinPred
0.97
D
GERP RS
5.6
Varity_R
0.63
gMVP
0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs864321678; hg19: chr6-42930587; API