rs138613460
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NMNAT1 | NM_022787.4 | c.37G>A | p.Ala13Thr | missense_variant | 2/5 | ENST00000377205.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NMNAT1 | ENST00000377205.6 | c.37G>A | p.Ala13Thr | missense_variant | 2/5 | 1 | NM_022787.4 | P1 | |
NMNAT1 | ENST00000403197.5 | c.37G>A | p.Ala13Thr | missense_variant | 2/5 | 2 | |||
NMNAT1 | ENST00000492735.1 | n.121G>A | non_coding_transcript_exon_variant | 2/2 | 3 | ||||
NMNAT1 | ENST00000462686.1 | c.37G>A | p.Ala13Thr | missense_variant, NMD_transcript_variant | 2/6 | 5 |
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
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | May 10, 2021 | ACMG classification criteria: PS4 supporting, PM3 strong, PP3 supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | 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; Invitae). 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). 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 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. - |
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 29, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 09, 2022 | PM3, BS3, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2019 | Functional studies of A13T indicate that mutant NMNAT protein expression and activity is similar to wild type (Sasaki et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26018082, 22842229, 22842230, 22842227, 32865313) - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 05, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at