rs150726175
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4
The NM_022787.4(NMNAT1):c.769G>A(p.Glu257Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 1 hom. )
Consequence
NMNAT1
NM_022787.4 missense
NM_022787.4 missense
Scores
2
3
13
Clinical Significance
Conservation
PhyloP100: 4.29
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a helix (size 3) in uniprot entity NMNA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_022787.4
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-9982630-G-A is Pathogenic according to our data. Variant chr1-9982630-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9982630-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9982630-G-A is described in Lovd as [Pathogenic]. Variant chr1-9982630-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9982630-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.025944293). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NMNAT1 | NM_022787.4 | c.769G>A | p.Glu257Lys | missense_variant | 5/5 | ENST00000377205.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NMNAT1 | ENST00000377205.6 | c.769G>A | p.Glu257Lys | missense_variant | 5/5 | 1 | NM_022787.4 | P1 | |
NMNAT1 | ENST00000496751.1 | c.119+1460G>A | intron_variant | 2 | |||||
NMNAT1 | ENST00000462686.1 | c.769G>A | p.Glu257Lys | missense_variant, NMD_transcript_variant | 5/6 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000815 AC: 124AN: 152158Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
124
AN:
152158
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000702 AC: 176AN: 250656Hom.: 0 AF XY: 0.000774 AC XY: 105AN XY: 135702
GnomAD3 exomes
AF:
AC:
176
AN:
250656
Hom.:
AF XY:
AC XY:
105
AN XY:
135702
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00103 AC: 1505AN: 1461870Hom.: 1 Cov.: 31 AF XY: 0.00101 AC XY: 731AN XY: 727244
GnomAD4 exome
AF:
AC:
1505
AN:
1461870
Hom.:
Cov.:
31
AF XY:
AC XY:
731
AN XY:
727244
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000814 AC: 124AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47AN XY: 74444
GnomAD4 genome
?
AF:
AC:
124
AN:
152276
Hom.:
Cov.:
32
AF XY:
AC XY:
47
AN XY:
74444
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
8
ALSPAC
AF:
AC:
6
ESP6500AA
AF:
AC:
3
ESP6500EA
AF:
AC:
11
ExAC
?
AF:
AC:
75
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leber congenital amaurosis 9 Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 257 of the NMNAT1 protein (p.Glu257Lys). This variant is present in population databases (rs150726175, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Leber congenital amaurosis (LCA), retinitis pigmentosa, and cone-rod dystrophy (PMID: 22842227, 22842229, 22842230, 22842231, 23040504, 24625443, 24940029, 26103963, 27032803). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NMNAT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NMNAT1 function (PMID: 22842230, 26018082). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Leber congenital amaurosis Pathogenic:3
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2016 | The p.Glu257Lys variant in NMNAT1 has been reported in >20 compound heterozygous individuals with Leber congenital amaurosis (LCA) and was the most frequent NMN AT1 variant identified in patients (Chiang 2012, Falk 2012, Koenekoop 2012, Perr ault 2012, Siemiatkowska 2014). In addition, in vitro functional studies provide some evidence that the p.Glu257Lys variant may impact protein function (Sasaki 2015). This variant has also been identified in 0.06% (74/120,500) of chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs150726175). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. However, available data suggests that this variant only causes disease when the re is a severe pathogenic variant on the opposite allele (Siemiatkowska 2014). I ndividuals homozygous for this variant are not expected to be affected with LCA. In summary, the p.Glu257Lys variant meets our criteria to be classified as pat hogenic for LCA in an autosomal recessive manner based upon its identification i n affected individuals in trans with other disease-associated variants, low freq uency in controls, and functional evidence. - |
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2021 | Published functional studies demonstrate a damaging effect with p.(E257K) resulting in abnormal protein folding, a less stable protein under thermal stress, and significantly reduced enzymatic activity (Koenekoop et al., 2012; Sasaki et al., 2015); This variant is associated with the following publications: (PMID: 24940029, 24830548, 28224992, 22842231, 32150116, 32507954, 22842227, 26018082, 22842229, 27032803, 29184169, 29178642, 24625443, 28492532, 30609409, 28559085, 30576320, 29674119, 31456290, 31980526, 32581362, 34426522, 31589614, 32865313, 32037395, 30004997, 22842230) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 09, 2023 | - - |
Diarrhea;C0028738:Nystagmus;C0557874:Global developmental delay;C0854723:Retinal dystrophy;C1301509:Severely reduced visual acuity;C1836830:Developmental regression;C1836923:Gastrointestinal dysmotility Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 19, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at