chr11-114312218-C-T

Variant names:

• chr11-114312218-C-T
• rs375878881
• NM_006169.3:c.536C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006169.3(NNMT):​c.536C>T​(p.Ala179Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,614,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A179S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: NNMT NM_006169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65
• Publications: 2 publications found

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]

ENSG00000256947 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19993731).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006169.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNMT	NM_006169.3	MANE Select	c.536C>T	p.Ala179Val	missense	Exon 3 of 3	NP_006160.1	P40261
	NNMT	NM_001372045.1		c.536C>T	p.Ala179Val	missense	Exon 4 of 4	NP_001358974.1	P40261
	NNMT	NM_001372046.1		c.536C>T	p.Ala179Val	missense	Exon 4 of 4	NP_001358975.1	P40261

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NNMT	ENST00000299964.4	TSL:1 MANE Select	c.536C>T	p.Ala179Val	missense	Exon 3 of 3	ENSP00000299964.3	P40261
	NNMT	ENST00000535401.5	TSL:1	c.536C>T	p.Ala179Val	missense	Exon 5 of 5	ENSP00000441434.1	P40261
	NNMT	ENST00000713573.1		c.536C>T	p.Ala179Val	missense	Exon 3 of 3	ENSP00000518865.1	P40261

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251226 AF XY: 0.000214

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000193 AC: 282 AN: 1461864 Hom.: 1 Cov.: 31 AF XY: 0.000194 AC XY: 141 AN XY: 727230

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53404

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000205 AC: 228 AN: 1112004

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74484

African (AFR) AF: 0.000289 AC: 12 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Benign	0.053	T
Sift4G	Benign	0.071	T
Polyphen		1.0	D
Vest4		0.27
MVP		0.18
MPC		0.013
ClinPred		0.096	T
GERP RS		3.1
Varity_R		0.33
gMVP		0.15
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs375878881; hg19: chr11-114182940;