chr11-114312103-T-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006169.3(NNMT):c.421T>A(p.Cys141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,611,196 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
NNMT
NM_006169.3 missense
NM_006169.3 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 3.36
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NNMT | NM_006169.3 | c.421T>A | p.Cys141Ser | missense_variant | 3/3 | ENST00000299964.4 | NP_006160.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NNMT | ENST00000299964.4 | c.421T>A | p.Cys141Ser | missense_variant | 3/3 | 1 | NM_006169.3 | ENSP00000299964.3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249692Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134840
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459002Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 725330
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
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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 submitter | clinical testing | Ambry Genetics | Nov 21, 2024 | The c.421T>A (p.C141S) alteration is located in exon 3 (coding exon 3) of the NNMT gene. This alteration results from a T to A substitution at nucleotide position 421, causing the cysteine (C) at amino acid position 141 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at