1-9972131-A-G

Variant names:

• chr1-9972131-A-G
• rs201530407
• NM_022787.4:c.58A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_022787.4(NMNAT1):​c.58A>G​(p.Ile20Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,460,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I20N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: NMNAT1 NM_022787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02

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 5 ACMG points.

• PM1: In a chain Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (size 278) in uniprot entity NMNA1_HUMAN there are 124 pathogenic changes around while only 6 benign (95%) in NM_022787.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29550362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT1	NM_022787.4	c.58A>G	p.Ile20Val	missense_variant	Exon 2 of 5	ENST00000377205.6	NP_073624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMNAT1	ENST00000377205.6	c.58A>G	p.Ile20Val	missense_variant	Exon 2 of 5	1	NM_022787.4	ENSP00000366410.1
NMNAT1	ENST00000403197.5	c.58A>G	p.Ile20Val	missense_variant	Exon 2 of 5	2		ENSP00000385131.1
NMNAT1	ENST00000462686.1	n.58A>G		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000435134.1
NMNAT1	ENST00000492735.1	n.142A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1460446 Hom.: 0 Cov.: 29 AF XY: 0.0000206 AC XY: 15 AN XY: 726678

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58A>G (p.I20V) alteration is located in exon 2 (coding exon 1) of the NMNAT1 gene. This alteration results from a A to G substitution at nucleotide position 58, causing the isoleucine (I) at amino acid position 20 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.6	.;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.85	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.32	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.17	.;B
Vest4		0.26
MutPred		0.71		Loss of catalytic residue at L25 (P = 0.0736);Loss of catalytic residue at L25 (P = 0.0736);
MVP		0.68
MPC		0.048
ClinPred		0.55	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.66

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: rs201530407; hg19: chr1-10032189;