1-9972095-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_022787.4(NMNAT1):c.22G>A(p.Glu8Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E8A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NMNAT1 NM_022787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.11546981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NMNAT1	NM_022787.4	c.22G>A	p.Glu8Lys	missense_variant	2/5	ENST00000377205.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NMNAT1	ENST00000377205.6	c.22G>A	p.Glu8Lys	missense_variant	2/5	1	NM_022787.4	P1
NMNAT1	ENST00000403197.5	c.22G>A	p.Glu8Lys	missense_variant	2/5	2
NMNAT1	ENST00000492735.1	n.106G>A		non_coding_transcript_exon_variant	2/2	3
NMNAT1	ENST00000462686.1	c.22G>A	p.Glu8Lys	missense_variant, NMD_transcript_variant	2/6	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 1022764). This variant has not been reported in the literature in individuals affected with NMNAT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 8 of the NMNAT1 protein (p.Glu8Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Benign	0.74
DEOGEN2	Benign	0.0096	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	0.057	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.81	N;N
REVEL	Uncertain	0.41
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.016	.;B
Vest4		0.24
MutPred		0.43		Gain of methylation at E8 (P = 0.0062);Gain of methylation at E8 (P = 0.0062);
MVP		0.97
MPC		0.097
ClinPred		0.69	D
GERP RS		3.9
Varity_R		0.31
gMVP		0.76

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: rs1641702008; hg19: chr1-10032153;