1-9982688-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_022787.4(NMNAT1):​c.827A>T​(p.Glu276Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. E276A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NMNAT1
NM_022787.4 missense

Scores

7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14
Variant links:
Genes affected
NMNAT1 (HGNC:17877): (nicotinamide nucleotide adenylyltransferase 1) This gene encodes an enzyme which catalyzes a key step in the biosynthesis of nicotinamide adenine dinucleotide (NAD). The encoded enzyme is one of several nicotinamide nucleotide adenylyltransferases, and is specifically localized to the cell nucleus. Activity of this protein leads to the activation of a nuclear deacetylase that functions in the protection of damaged neurons. Mutations in this gene have been associated with Leber congenital amaurosis 9. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are located on chromosomes 1, 3, 4, 14, and 15. [provided by RefSeq, Jul 2014]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a chain Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (size 278) in uniprot entity NMNA1_HUMAN there are 122 pathogenic changes around while only 6 benign (95%) in NM_022787.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1673117).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NMNAT1NM_022787.4 linkc.827A>T p.Glu276Val missense_variant Exon 5 of 5 ENST00000377205.6 NP_073624.2 Q9HAN9A0A024R4E1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NMNAT1ENST00000377205.6 linkc.827A>T p.Glu276Val missense_variant Exon 5 of 5 1 NM_022787.4 ENSP00000366410.1 Q9HAN9
NMNAT1ENST00000496751.1 linkc.118+1518A>T intron_variant Intron 1 of 1 2 ENSP00000467340.1 K7EPD7
NMNAT1ENST00000462686.1 linkn.827A>T non_coding_transcript_exon_variant Exon 5 of 6 5 ENSP00000435134.1 Q9HAN9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Leber congenital amaurosis 9 Uncertain:1
Jun 22, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NMNAT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 276 of the NMNAT1 protein (p.Glu276Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.087
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
9.6
DANN
Uncertain
0.98
DEOGEN2
Benign
0.023
T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.24
N
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.17
T
MetaSVM
Uncertain
0.43
D
MutationAssessor
Uncertain
2.0
M
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.25
Sift
Uncertain
0.010
D
Sift4G
Uncertain
0.049
D
Polyphen
0.36
B
Vest4
0.17
MutPred
0.18
Gain of MoRF binding (P = 0.0115);
MVP
0.91
MPC
0.11
ClinPred
0.12
T
GERP RS
2.6
Varity_R
0.11
gMVP
0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-10042746; API