1-9982630-G-A

Position:

chr1-9982630-G-A

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

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

NMNAT1
NM_022787.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 4.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a helix (size 3) in uniprot entity NMNA1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_022787.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-9982630-G-A is Pathogenic according to our data. Variant chr1-9982630-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9982630-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9982630-G-A is described in Lovd as [Pathogenic]. Variant chr1-9982630-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9982630-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.025944293). . 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.769G>A	p.Glu257Lys	missense_variant	5/5	ENST00000377205.6	NP_073624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NMNAT1	ENST00000377205.6 linkuse as main transcript	c.769G>A	p.Glu257Lys	missense_variant	5/5	1	NM_022787.4	ENSP00000366410	P1
NMNAT1	ENST00000496751.1 linkuse as main transcript	c.119+1460G>A		intron_variant		2		ENSP00000467340
NMNAT1	ENST00000462686.1 linkuse as main transcript	c.769G>A	p.Glu257Lys	missense_variant, NMD_transcript_variant	5/6	5		ENSP00000435134

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.000918

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:

0.00129

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000702

AC:

176

AN:

250656

Hom.:

AF XY:

0.000774

AC XY:

105

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.00103

AC:

1505

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

731

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000814

AC:

124

AN:

152276

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000917

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000774

Hom.:

Bravo

AF:

0.000801

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000618

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.00113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 9

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	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). 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 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. -

Leber congenital amaurosis

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2016	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

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

Diarrhea;C0028738:Nystagmus;C0557874:Global developmental delay;C0854723:Retinal dystrophy;C1301509:Severely reduced visual acuity;C1836830:Developmental regression;C1836923:Gastrointestinal dysmotility

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2024

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

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. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.0040

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

Eigen

Benign

-0.079

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.059

MetaRNN

Benign

0.026

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.69

Sift

Benign

0.53

Sift4G

Benign

0.38

Polyphen

0.089

Vest4

0.37

MVP

0.95

MPC

0.051

ClinPred

0.35

GERP RS

5.0

Varity_R

0.30

gMVP

0.67

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