chr1-9982480-C-T

Position:

chr1-9982480-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_022787.4(NMNAT1):c.619C>T(p.Arg207Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NMNAT1
NM_022787.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.06

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 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_022787.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-9982480-C-T is Pathogenic according to our data. Variant chr1-9982480-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9982480-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-9982480-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-9982480-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NMNAT1	NM_022787.4 linkuse as main transcript	c.619C>T	p.Arg207Trp	missense_variant	5/5	ENST00000377205.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NMNAT1	ENST00000377205.6 linkuse as main transcript	c.619C>T	p.Arg207Trp	missense_variant	5/5	1	NM_022787.4	P1
NMNAT1	ENST00000496751.1 linkuse as main transcript	c.119+1310C>T		intron_variant		2
NMNAT1	ENST00000462686.1 linkuse as main transcript	c.619C>T	p.Arg207Trp	missense_variant, NMD_transcript_variant	5/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251416

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000279

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000749

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	Published functional studies demonstrate a damaging effect on enzyme activity (Koenekoop RK1 et al., 2012); 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: 26103963, 28559085, 24940029, 31589614, 34426522, 22842230, 22842229, 26018082) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Leber congenital amaurosis 9

Pathogenic:3

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 207 of the NMNAT1 protein (p.Arg207Trp). This variant is present in population databases (rs142968179, gnomAD 0.007%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 22842229, 22842230, 24940029). 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: 37133). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NMNAT1 protein function. Experimental studies have shown that this missense change affects NMNAT1 function (PMID: 22842230). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Benign

0.013

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.47

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.93

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

0.21

Vest4

0.17

MVP

0.98

MPC

0.047

ClinPred

0.37

GERP RS

3.0

Varity_R

0.40

gMVP

0.80

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