rs150726175

chr1-9982630-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 3) in uniprot entity NMNA1_HUMAN there are 5 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	UniProt
NMNAT1	NM_022787.4	c.769G>A	p.Glu257Lys	missense_variant	5/5	ENST00000377205.6

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152158 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000774 AC XY: 105 AN XY: 135702

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.: 1 Cov.: 31 AF XY: 0.00101 AC XY: 731 AN XY: 727244

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.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74444

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.: 0

Bravo AF: 0.000801

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.00131

EpiControl AF: 0.00113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 9 Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -

Leber congenital amaurosis Pathogenic:3

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
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

-

- -

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	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.079
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.69
Sift	Benign	0.53	T
Sift4G	Benign	0.38	T
Polyphen		0.089	B
Vest4		0.37
MVP		0.95
MPC		0.051
ClinPred		0.35	T
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

Other links and lift over

dbSNP: rs150726175; hg19: chr1-10042688;