1-9972074-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_022787.4(NMNAT1):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000568 in 1,409,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: NMNAT1 NM_022787.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.64

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-9972074-A-G is Pathogenic according to our data. Variant chr1-9972074-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 978252.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-9972074-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NMNAT1	NM_022787.4	c.1A>G	p.Met1?	start_lost	2/5	ENST00000377205.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NMNAT1	ENST00000377205.6	c.1A>G	p.Met1?	start_lost	2/5	1	NM_022787.4	P1
NMNAT1	ENST00000403197.5	c.1A>G	p.Met1?	start_lost	2/5	2
NMNAT1	ENST00000492735.1	n.85A>G		non_coding_transcript_exon_variant	2/2	3
NMNAT1	ENST00000462686.1	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	2/6	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250540 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000568 AC: 8 AN: 1409234 Hom.: 0 Cov.: 25 AF XY: 0.00000568 AC XY: 4 AN XY: 704228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000658

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leber congenital amaurosis 9 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Genetics in Ophthalmology, Institut Imagine

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.091	T;D
Polyphen		0.67	.;P
Vest4		0.89
MutPred		0.98		Loss of methylation at K6 (P = 0.2767);Loss of methylation at K6 (P = 0.2767);
MVP		0.98
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.85

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: rs756649389; hg19: chr1-10032132;