rs387907293

Variant names:

• chr1-9982318-C-A
• rs387907293
• NM_022787.4:c.457C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-9982318-C-A
• chr1-9982318-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_022787.4(NMNAT1):​c.457C>A​(p.Leu153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,308 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L153P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NMNAT1 NM_022787.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.164
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Leber congenital amaurosis 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• NMNAT1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-9982319-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 978240.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.62663 (below the threshold of 3.09). Trascript score misZ: 1.2512 (below the threshold of 3.09). GenCC associations: The gene is linked to NMNAT1-related retinopathy, Leber congenital amaurosis 9, cone-rod dystrophy, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, Leber congenital amaurosis.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT1	NM_022787.4	c.457C>A	p.Leu153Met	missense_variant	Exon 5 of 5	ENST00000377205.6	NP_073624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMNAT1	ENST00000377205.6	c.457C>A	p.Leu153Met	missense_variant	Exon 5 of 5	1	NM_022787.4	ENSP00000366410.1
NMNAT1	ENST00000462686.1	n.457C>A		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000435134.1
NMNAT1	ENST00000496751.1	c.118+1148C>A		intron_variant	Intron 1 of 1	2		ENSP00000467340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460308 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726324

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111034

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.71	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		-0.16
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.048	D
Polyphen		0.97	D
Vest4		0.37
MutPred		0.70		Gain of catalytic residue at L153 (P = 9e-04);
MVP		0.84
MPC		0.30
ClinPred		0.99	D
GERP RS		-6.3
Varity_R		0.70
gMVP		0.77
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387907293; hg19: chr1-10042376;