1-183286683-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_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

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.848

Publications

1 publications found

Variant links:

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]

NMNAT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.427G>A	p.Val143Met	missense_variant	Exon 5 of 11	ENST00000287713.7	NP_055854.1	Q9BZQ4-1
NMNAT2	NM_170706.4 link	c.412G>A	p.Val138Met	missense_variant	Exon 5 of 11		NP_733820.1	Q9BZQ4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NMNAT2	ENST00000287713.7 link	c.427G>A	p.Val143Met	missense_variant	Exon 5 of 11	1	NM_015039.4	ENSP00000287713.6	Q9BZQ4-1
NMNAT2	ENST00000294868.8 link	c.412G>A	p.Val138Met	missense_variant	Exon 5 of 11	1		ENSP00000294868.4	Q9BZQ4-2
NMNAT2	ENST00000473046.1 link	n.297G>A		non_coding_transcript_exon_variant	Exon 3 of 5	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

247954

AF XY:

0.00

show subpopulations

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:

AN:

1458156

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725302

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33406

American (AMR)

AF:

0.0000227

AC:

AN:

44090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85270

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110306

Other (OTH)

AF:

0.00

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

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

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.015

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.2

.;L

PhyloP100

0.85

PrimateAI

Benign

0.43

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

GERP RS

5.7

Varity_R

0.076

gMVP

0.51

Mutation Taster

=88/12

polymorphism

(source)

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

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1-183286683-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over