rs150726175
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
Consequence
NM_022787.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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NMNAT1 | NM_022787.4 | c.769G>A | p.Glu257Lys | missense_variant | Exon 5 of 5 | ENST00000377205.6 | NP_073624.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NMNAT1 | ENST00000377205.6 | c.769G>A | p.Glu257Lys | missense_variant | Exon 5 of 5 | 1 | NM_022787.4 | ENSP00000366410.1 | ||
NMNAT1 | ENST00000496751.1 | c.118+1460G>A | intron_variant | Intron 1 of 1 | 2 | ENSP00000467340.1 | ||||
NMNAT1 | ENST00000462686.1 | n.769G>A | non_coding_transcript_exon_variant | Exon 5 of 6 | 5 | ENSP00000435134.1 |
Frequencies
GnomAD3 genomes AF: 0.000815 AC: 124AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000702 AC: 176AN: 250656Hom.: 0 AF XY: 0.000774 AC XY: 105AN XY: 135702
GnomAD4 exome AF: 0.00103 AC: 1505AN: 1461870Hom.: 1 Cov.: 31 AF XY: 0.00101 AC XY: 731AN XY: 727244
GnomAD4 genome AF: 0.000814 AC: 124AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47AN XY: 74444
ClinVar
Submissions by phenotype
Leber congenital amaurosis 9 Pathogenic:5Other:1
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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Leber congenital amaurosis Pathogenic:3
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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. -
not provided Pathogenic:3
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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) -
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Retinal dystrophy Pathogenic:2
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Diarrhea;C0028738:Nystagmus;C0557874:Global developmental delay;C0854723:Retinal dystrophy;C1301509:Severely reduced visual acuity;C1836830:Developmental regression;C1836923:Gastrointestinal dysmotility Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.769G>A (p.E257K) alteration is located in exon 5 (coding exon 4) of the NMNAT1 gene. This alteration results from a G to A substitution at nucleotide position 769, causing the glutamic acid (E) at amino acid position 257 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.07% (196/282064) total alleles studied. The highest observed frequency was 0.122% (157/128844) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other NMNAT1 variants in individuals with features consistent with NMNAT1-related retinopathy; in at least one instance, the variants were identified in trans (Chiang, 2012; Koenekoop, 2012; Perrault, 2012). This amino acid position is well conserved in available vertebrate species. Functional studies have demonstrated this variant affects enzyme function (Koenekoop, 2012; Sasaki, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
NMNAT1-related disorder Pathogenic:1
The NMNAT1 c.769G>A variant is predicted to result in the amino acid substitution p.Glu257Lys. This variant has been reported along with a second NMNAT1 variant many times in individuals with Leber congenital amaurosis (see for examples Table S3 in Perrault et al. 2012. PubMed ID: 22842229; Chiang et al. 2012. PubMed ID: 22842231; Falk et al. 2012. PubMed ID: 22842227). Both in vivo and in vitro assays have indicated that this variant significantly reduces enzymatic activity compared to the wild-type protein (Koenekoop et al. 2012. PubMed ID: 22842230). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is relatively common; this variant has been suggested to be a founder variant (Koenekoop et al. 2012. PubMed ID: 22842230). The high frequency of the variant and the detection of this variant in the homozygous state in at least one unaffected individual indicates a reduced penetrance; it has been proposed that p.Gly257Lys is a hypomorphic allele that only causes disease when in trans with a more severe variant (Siemiatkowska et al. 2014. PubMed ID: 24830548). Given the evidence, we interpret this variant as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at