rs199765030

Variant names:

• chr1-183286683-C-T
• rs199765030
• NM_015039.4:c.427G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_015039.4(NMNAT2):​c.427G>A​(p.Val143Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,458,156 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NMNAT2 NM_015039.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.848
• Publications: 1 publications found

Genes affected

NMNAT2 (HGNC:16789): (nicotinamide nucleotide adenylyltransferase 2) This gene product belongs to the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyze an essential step in NAD (NADP) biosynthetic pathway. Unlike the other human family member, which is localized to the nucleus, and is ubiquitously expressed; this enzyme is cytoplasmic, and is predominantly expressed in the brain. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1005 (below the threshold of 3.09). Trascript score misZ: 2.0325 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.1417669).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT2	NM_015039.4	c.427G>A	p.Val143Met	missense_variant	Exon 5 of 11	ENST00000287713.7	NP_055854.1
NMNAT2	NM_170706.4	c.412G>A	p.Val138Met	missense_variant	Exon 5 of 11		NP_733820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMNAT2	ENST00000287713.7	c.427G>A	p.Val143Met	missense_variant	Exon 5 of 11	1	NM_015039.4	ENSP00000287713.6
NMNAT2	ENST00000294868.8	c.412G>A	p.Val138Met	missense_variant	Exon 5 of 11	1		ENSP00000294868.4
NMNAT2	ENST00000473046.1	n.297G>A		non_coding_transcript_exon_variant	Exon 3 of 5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247954 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1458156 Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7 AN XY: 725302

African (AFR) AF: 0.0000299 AC: 1 AN: 33406

American (AMR) AF: 0.0000227 AC: 1 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39606

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85270

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110306

Other (OTH) AF: 0.00 AC: 0 AN: 60264

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Vascular dementia Uncertain:1

Oct 01, 2021

Myllykangas group, University of Helsinki

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.2	.;L
PhyloP100		0.85
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.17	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.12	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.22	B;B
Vest4		0.22
MutPred		0.54		.;Loss of sheet (P = 0.0315);
MVP		0.66
MPC		0.85
ClinPred		0.20	T
GERP RS		5.7
Varity_R		0.076
gMVP		0.51
Mutation Taster		=88/12	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: rs199765030; hg19: chr1-183255818; COSMIC: COSV105138468;