NM_022787.4:c.838T>C

Variant names:

• chr1-9982699-T-C
• rs387907290
• NM_022787.4:c.838T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_022787.4(NMNAT1):​c.838T>C​(p.Ter280Glnext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,370 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NMNAT1 NM_022787.4 stop_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0980
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_022787.4 Downstream stopcodon found after 311 codons.
• PP5: Variant 1-9982699-T-C is Pathogenic according to our data. Variant chr1-9982699-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 37132.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT1	NM_022787.4	c.838T>C	p.Ter280Glnext*?	stop_lost	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.838T>C	p.Ter280Glnext*?	stop_lost	Exon 5 of 5	1	NM_022787.4	ENSP00000366410.1
NMNAT1	ENST00000462686.1	n.838T>C		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000435134.1
NMNAT1	ENST00000496751.1	c.118+1529T>C		intron_variant	Intron 1 of 1	2		ENSP00000467340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445370 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717692

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 41866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 84042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103688

Other (OTH) AF: 0.00 AC: 0 AN: 59594

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leber congenital amaurosis 9 Pathogenic:1

Sep 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.6
DANN	Benign	0.84
Eigen	Benign	0.094
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.056	N
PhyloP100		-0.098
Vest4		0.045
GERP RS		-0.80
Mutation Taster		=54/146	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907290; hg19: chr1-10042757;