rs371526758

Positions:

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

5
1
1

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]

Genome browser will be placed here

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
NMNAT1NM_022787.4 linkuse as main transcriptc.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 Appris UniProt
NMNAT1ENST00000377205.6 linkuse as main transcriptc.507G>A p.Trp169* stop_gained 5/51 NM_022787.4 ENSP00000366410.1 Q9HAN9
NMNAT1ENST00000496751.1 linkuse as main transcriptc.118+1198G>A intron_variant 2 ENSP00000467340.1 K7EPD7
NMNAT1ENST00000462686.1 linkuse as main transcriptn.507G>A non_coding_transcript_exon_variant 5/65 ENSP00000435134.1 Q9HAN9

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152174
Hom.:
0
Cov.:
32
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:
10
AN:
251430
Hom.:
0
AF XY:
0.0000442
AC XY:
6
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:
60
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.0000385
AC XY:
28
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:
17
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
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.:
0
Bravo
AF:
0.000125
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000165
AC:
2
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 providedliterature onlyOMIMSep 01, 2012- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 27, 2023This 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 providedresearchLaboratory of Genetics in Ophthalmology, Institut Imagine-- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 24, 2024The 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 providedclinical testingPreventionGenetics, part of Exact SciencesSep 13, 2024The 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 submitterclinical testingGeneDxApr 30, 2019Nonsense 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
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
1.0
D
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.

Other links and lift over

dbSNP: rs371526758; hg19: chr1-10042426; API