rs138613460

Variant names:

• chr1-9972110-G-A
• rs138613460
• NM_022787.4:c.37G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM5 PP2 PP3 PP5 BP4

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. A13G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: NMNAT1 NM_022787.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:4
• Conservation: PhyloP100: 9.56
• Publications: 6 publications found

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]

NMNAT1 Gene-Disease associations (from GenCC):

• Leber congenital amaurosis 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• NMNAT1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_022787.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-9972111-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1376825.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.62663 (below the threshold of 3.09). Trascript score misZ: 1.2512 (below the threshold of 3.09). GenCC associations: The gene is linked to NMNAT1-related retinopathy, Leber congenital amaurosis 9, cone-rod dystrophy, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, Leber congenital amaurosis.
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-9972110-G-A is Pathogenic according to our data. Variant chr1-9972110-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195375.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18942168). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMNAT1	NM_022787.4	MANE Select	c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	NP_073624.2
	NMNAT1	NM_001297778.1		c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	NP_001284707.1
	NMNAT1	NM_001297779.2		c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	NP_001284708.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMNAT1	ENST00000377205.6	TSL:1 MANE Select	c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	ENSP00000366410.1
	NMNAT1	ENST00000403197.5	TSL:2	c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	ENSP00000385131.1
	NMNAT1	ENST00000462686.1	TSL:5	n.37G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000435134.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 251108 AF XY: 0.000125

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1460506 Hom.: 0 Cov.: 28 AF XY: 0.0000578 AC XY: 42 AN XY: 726640

African (AFR) AF: 0.00224 AC: 75 AN: 33444

American (AMR) AF: 0.000157 AC: 7 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110828

Other (OTH) AF: 0.0000663 AC: 4 AN: 60328

GnomAD4 genome AF: 0.000539 AC: 82 AN: 152208 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74408

African (AFR) AF: 0.00193 AC: 80 AN: 41536

American (AMR) AF: 0.000131 AC: 2 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000783 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leber congenital amaurosis 9 Pathogenic:6

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 10, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 supporting, PM3 strong, PP3 supporting

May 04, 2022

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 26, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.011%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.87 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000195375 /PMID: 22842229). A different missense change at the same codon (p.Ala13Asp) has been reported to be associated with NMNAT1 related disorder (ClinVar ID: VCV001376825). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:1 Uncertain:2

Jan 29, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 09, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, BS3, PP3

Jun 26, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1 Uncertain:1

Jan 05, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2020

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NMNAT1-related disorder Uncertain:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.19	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.98
MPC		0.30
ClinPred		0.25	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.84
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138613460; hg19: chr1-10032168;