1-9982368-G-A

Position:

chr1-9982368-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_022787.4(NMNAT1):c.507G>A(p.Trp169*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

NMNAT1
NM_022787.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.70

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 70 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-9982368-G-A is Pathogenic according to our data. Variant chr1-9982368-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9982368-G-A is described in Lovd as [Pathogenic]. Variant chr1-9982368-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9982368-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9982368-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMNAT1	NM_022787.4 linkuse as main transcript	c.507G>A	p.Trp169*	stop_gained	5/5	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.507G>A	p.Trp169*	stop_gained	5/5	1	NM_022787.4	ENSP00000366410.1	Q9HAN9
NMNAT1	ENST00000496751.1 linkuse as main transcript	c.118+1198G>A		intron_variant		2		ENSP00000467340.1	K7EPD7
NMNAT1	ENST00000462686.1 linkuse as main transcript	n.507G>A		non_coding_transcript_exon_variant	5/6	5		ENSP00000435134.1	Q9HAN9

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251430

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

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:

0.0000477

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000112

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000639

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 9

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2023	This variant is present in population databases (rs371526758, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Trp169*) in the NMNAT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 111 amino acid(s) of the NMNAT1 protein. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265453). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 22842229, 22842230, 22842231, 29178642). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2024

The c.507G>A (p.W169*) alteration, located in exon 5 (coding exon 4) of the NMNAT1 gene, consists of a G to A substitution at nucleotide position 507. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 169. This alteration occurs at the 3' terminus of the NMNAT1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 40% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (12/282830) total alleles studied. The highest observed frequency was 0.008% (10/129152) 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 (Koenekoop, 2012; Chiang, 2012; Perrault, 2012). 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.507G>A variant is predicted to result in premature protein termination (p.Trp169*). This variant has been reported in the homozygous and compound heterozygous states in individuals with Leber congenital amaurosis (Chiang et al. 2012. PubMed ID: 22842231; Perrault et al. 2012. PubMed ID: 22842229; Koenekoop et al. 2012. PubMed ID: 22842230; Table S4, Stone et al. 2017. PubMed ID: 28559085). This variant has also been reported in the absence of a second NMNAT1 variant in an individual with macular atrophy with pigmentary clumping (Table S3, Perrault et al. 2012. PubMed ID: 22842229). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in NMNAT1 are an established mechanism of disease. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2019

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 111 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database(Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22842230, 22842231, 22842229, 29178642, 28559085, 31589614, 32865313) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

1.0

Vest4

0.80

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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