NM_022787.4:c.37G>A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM2PM5PP3PP5BP4
The NM_022787.4(NMNAT1):c.37G>A(p.Ala13Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,612,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_022787.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NMNAT1 | NM_022787.4 | c.37G>A | p.Ala13Thr | missense_variant | Exon 2 of 5 | ENST00000377205.6 | NP_073624.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NMNAT1 | ENST00000377205.6 | c.37G>A | p.Ala13Thr | missense_variant | Exon 2 of 5 | 1 | NM_022787.4 | ENSP00000366410.1 | ||
NMNAT1 | ENST00000403197.5 | c.37G>A | p.Ala13Thr | missense_variant | Exon 2 of 5 | 2 | ENSP00000385131.1 | |||
NMNAT1 | ENST00000462686.1 | n.37G>A | non_coding_transcript_exon_variant | Exon 2 of 6 | 5 | ENSP00000435134.1 | ||||
NMNAT1 | ENST00000492735.1 | n.121G>A | non_coding_transcript_exon_variant | Exon 2 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000539 AC: 82AN: 152090Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251108Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135700
GnomAD4 exome AF: 0.0000630 AC: 92AN: 1460506Hom.: 0 Cov.: 28 AF XY: 0.0000578 AC XY: 42AN XY: 726640
GnomAD4 genome AF: 0.000539 AC: 82AN: 152208Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36AN XY: 74408
ClinVar
Submissions by phenotype
Leber congenital amaurosis 9 Pathogenic:4
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the NMNAT1 protein (p.Ala13Thr). This variant is present in population databases (rs138613460, gnomAD 0.2%). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 22842227, 22842229, 32865313; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195375). 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 expected to disrupt NMNAT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect NMNAT1 function (PMID: 26018082). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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ACMG classification criteria: PS4 supporting, PM3 strong, PP3 supporting -
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not provided Pathogenic:1Uncertain:2
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PM3, BS3, PP3 -
In a published functional study, this variant performed similar to wildtype, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 26018082); 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: 22842229, 22842227, 32641690, 32865313, 34041853, 22842230, 38219857, 26018082) -
Retinal dystrophy Pathogenic:1Uncertain:1
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NMNAT1-related disorder Uncertain:1
The NMNAT1 c.37G>A variant is predicted to result in the amino acid substitution p.Ala13Thr. This variant has been reported with another likely causative variant (three individuals who also carried the p.Val98Gly variant) or a variant of uncertain significance (one case) in patients with Leber congenital amaurosis (Supplementary Table 3 in Perrault et al. 2012. PubMed ID: 22842229, Table 1, P18; Falk et al. 2012. PubMed ID: 22842227, Table 1, LCA-3; Porto et al. 2017. PubMed ID: 29186038, Table 2, patient FBP_57; Koenekoop et al. 2012. PubMed ID: 22842230, Patient MOGL3698). Functional, expression, and localization studies suggested that this variant is similar to wild-type (Sasaki et al. 2015. PubMed ID: 26018082). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at