rs387907292

Positions:

• chr1-9982312-G-C
• chr1-9982312-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_022787.4(NMNAT1):​c.451G>C​(p.Val151Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V151F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NMNAT1 NM_022787.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.227

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 4 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, 3 uncertain 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 chr1-9982312-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.14145023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMNAT1	NM_022787.4	c.451G>C	p.Val151Leu	missense_variant	5/5	ENST00000377205.6	NP_073624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NMNAT1	ENST00000377205.6	c.451G>C	p.Val151Leu	missense_variant	5/5	1	NM_022787.4	ENSP00000366410.1
NMNAT1	ENST00000496751.1	c.118+1142G>C		intron_variant		2		ENSP00000467340.1
NMNAT1	ENST00000462686.1	n.451G>C		non_coding_transcript_exon_variant	5/6	5		ENSP00000435134.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	10
DANN	Benign	0.63
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.51	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.025	B
Vest4		0.086
MutPred		0.65		Gain of ubiquitination at K152 (P = 0.0597);
MVP		0.67
MPC		0.049
ClinPred		0.061	T
GERP RS		2.0
Varity_R		0.18
gMVP		0.61

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

Other links and lift over

dbSNP: rs387907292; hg19: chr1-10042370;