1-9972086-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.13G>A(p.Glu5Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,600,554 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NMNAT1 NM_022787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

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 1 benign, 3 uncertain in NM_022787.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12420565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NMNAT1	NM_022787.4	c.13G>A	p.Glu5Lys	missense_variant	2/5	ENST00000377205.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NMNAT1	ENST00000377205.6	c.13G>A	p.Glu5Lys	missense_variant	2/5	1	NM_022787.4	P1
NMNAT1	ENST00000403197.5	c.13G>A	p.Glu5Lys	missense_variant	2/5	2
NMNAT1	ENST00000492735.1	n.97G>A		non_coding_transcript_exon_variant	2/2	3
NMNAT1	ENST00000462686.1	c.13G>A	p.Glu5Lys	missense_variant, NMD_transcript_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250702 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135472

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000581

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000214 AC: 31 AN: 1448456 Hom.: 0 Cov.: 28 AF XY: 0.0000222 AC XY: 16 AN XY: 721444

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 5 of the NMNAT1 protein (p.Glu5Lys). This variant is present in population databases (rs747825699, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NMNAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 966992). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.0096	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	-0.14	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.74	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.33	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.010	.;B
Vest4		0.18
MutPred		0.31		Gain of methylation at E5 (P = 0.0056);Gain of methylation at E5 (P = 0.0056);
MVP		0.90
MPC		0.047
ClinPred		0.091	T
GERP RS		1.8
Varity_R		0.072
gMVP		0.57

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: rs747825699; hg19: chr1-10032144;