11-114312274-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006169.3(NNMT):​c.592G>A​(p.Ala198Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000050 ( 1 hom. )

Consequence

NNMT
NM_006169.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50
Variant links:
Genes affected
NNMT (HGNC:7861): (nicotinamide N-methyltransferase) N-methylation is one method by which drug and other xenobiotic compounds are metabolized by the liver. This gene encodes the protein responsible for this enzymatic activity which uses S-adenosyl methionine as the methyl donor. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08782935).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NNMTNM_006169.3 linkuse as main transcriptc.592G>A p.Ala198Thr missense_variant 3/3 ENST00000299964.4 NP_006160.1 P40261B0YJ53

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NNMTENST00000299964.4 linkuse as main transcriptc.592G>A p.Ala198Thr missense_variant 3/31 NM_006169.3 ENSP00000299964.3 P40261

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000995
AC:
25
AN:
251378
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000499
AC:
73
AN:
1461890
Hom.:
1
Cov.:
31
AF XY:
0.0000564
AC XY:
41
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00115
Gnomad4 EAS exome
AF:
0.000176
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152228
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000158
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 03, 2024The c.592G>A (p.A198T) alteration is located in exon 3 (coding exon 3) of the NNMT gene. This alteration results from a G to A substitution at nucleotide position 592, causing the alanine (A) at amino acid position 198 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.083
T;T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.53
D
LIST_S2
Benign
0.58
.;T
M_CAP
Benign
0.0066
T
MetaRNN
Benign
0.088
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.7
L;L
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.17
N;N
REVEL
Benign
0.12
Sift
Benign
0.89
T;T
Sift4G
Benign
0.72
T;T
Polyphen
0.23
B;B
Vest4
0.26
MutPred
0.49
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
0.076
MPC
0.0092
ClinPred
0.046
T
GERP RS
4.7
Varity_R
0.24
gMVP
0.20

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: rs777060632; hg19: chr11-114182996; API