rs138613460

Positions:

chr1-9972110-G-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

Genomes: 𝑓 0.00054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

NMNAT1
NM_022787.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:4

Conservation

PhyloP100: 9.56

Variant links:

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 links:

NMNAT1 (HGNC:):

NMNAT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 5 uncertain in NM_022787.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-9972111-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1376825.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, 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 id is 195375.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=4}. Variant chr1-9972110-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9972110-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.18942168). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMNAT1	NM_022787.4 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	2/5	ENST00000377205.6	NP_073624.2	Q9HAN9A0A024R4E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NMNAT1	ENST00000377205.6 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	2/5	1	NM_022787.4	ENSP00000366410.1	Q9HAN9
NMNAT1	ENST00000403197.5 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	2/5	2		ENSP00000385131.1	B1AN62
NMNAT1	ENST00000462686.1 linkuse as main transcript	n.37G>A		non_coding_transcript_exon_variant	2/6	5		ENSP00000435134.1	Q9HAN9
NMNAT1	ENST00000492735.1 linkuse as main transcript	n.121G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251108

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135700

show subpopulations

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 SAS 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:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726640

show subpopulations

Gnomad4 AFR exome

AF:

0.00224

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000539

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000555

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leber congenital amaurosis 9

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2024	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) -
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 -

Retinal dystrophy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 05, 2019	- -

NMNAT1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;.

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.19

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

.;H

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

.;D

Vest4

0.87

MVP

0.98

MPC

0.30

ClinPred

0.25

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over