rs142968179
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_022787.4(NMNAT1):c.619C>T(p.Arg207Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207Q) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
NMNAT1
NM_022787.4 missense
NM_022787.4 missense
Scores
6
7
5
Clinical Significance
Conservation
PhyloP100: 4.06
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 Pathogenic. Variant got 12 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_022787.4
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-9982480-C-T is Pathogenic according to our data. Variant chr1-9982480-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9982480-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-9982480-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-9982480-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NMNAT1 | NM_022787.4 | c.619C>T | p.Arg207Trp | missense_variant | 5/5 | ENST00000377205.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NMNAT1 | ENST00000377205.6 | c.619C>T | p.Arg207Trp | missense_variant | 5/5 | 1 | NM_022787.4 | P1 | |
NMNAT1 | ENST00000496751.1 | c.119+1310C>T | intron_variant | 2 | |||||
NMNAT1 | ENST00000462686.1 | c.619C>T | p.Arg207Trp | missense_variant, NMD_transcript_variant | 5/6 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152084Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251416Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135880
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727240
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74276
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | Published functional studies demonstrate a damaging effect on enzyme activity (Koenekoop RK1 et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26103963, 28559085, 24940029, 31589614, 34426522, 22842230, 22842229, 26018082) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Leber congenital amaurosis 9 Pathogenic:3
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 207 of the NMNAT1 protein (p.Arg207Trp). This variant is present in population databases (rs142968179, gnomAD 0.007%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 22842229, 22842230, 24940029). 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: 37133). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NMNAT1 protein function. Experimental studies have shown that this missense change affects NMNAT1 function (PMID: 22842230). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at