Genetic Variant NMNAT2:p.Arg64Leu (chr1-183292841-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_015039.4(NMNAT2):c.191G>T(p.Arg64Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R64Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

NMNAT2
NM_015039.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.30

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT2	NM_015039.4 link	c.191G>T	p.Arg64Leu	missense_variant	Exon 3 of 11	ENST00000287713.7	NP_055854.1	Q9BZQ4-1
NMNAT2	NM_170706.4 link	c.176G>T	p.Arg59Leu	missense_variant	Exon 3 of 11		NP_733820.1	Q9BZQ4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMNAT2	ENST00000287713.7 link	c.191G>T	p.Arg64Leu	missense_variant	Exon 3 of 11	1	NM_015039.4	ENSP00000287713.6		Q9BZQ4-1
NMNAT2	ENST00000294868.8 link	c.176G>T	p.Arg59Leu	missense_variant	Exon 3 of 11	1		ENSP00000294868.4		Q9BZQ4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250968

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

0.92

.;L

PhyloP100

5.3

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.9

N;N

REVEL

Pathogenic

0.74

Sift

Benign

0.21

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.99

D;D

Vest4

0.81

MutPred

0.41

.;Loss of solvent accessibility (P = 0.0544);

MVP

0.97

MPC

1.8

ClinPred

0.93

GERP RS

5.2

Varity_R

0.31

gMVP

0.91

Mutation Taster

=37/63

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over