chr1-9982597-G-C

Variant names:

• chr1-9982597-G-C
• rs747653875
• NM_022787.4:c.736G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP2 PP5 BP4

The NM_022787.4(NMNAT1):​c.736G>C​(p.Glu246Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NMNAT1 NM_022787.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.20
• 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: Uncertain_significance. The variant received 3 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, 2 uncertain in NM_022787.4
• 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.
• PP5: Variant 1-9982597-G-C is Pathogenic according to our data. Variant chr1-9982597-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438135.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1454776). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMNAT1	NM_022787.4	MANE Select	c.736G>C	p.Glu246Gln	missense	Exon 5 of 5	NP_073624.2
	NMNAT1	NM_001297778.1		c.736G>C	p.Glu246Gln	missense	Exon 5 of 5	NP_001284707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NMNAT1	ENST00000377205.6	TSL:1 MANE Select	c.736G>C	p.Glu246Gln	missense	Exon 5 of 5	ENSP00000366410.1
	NMNAT1	ENST00000462686.1	TSL:5	n.736G>C		non_coding_transcript_exon	Exon 5 of 6	ENSP00000435134.1
	NMNAT1	ENST00000496751.1	TSL:2	c.118+1427G>C		intron	N/A	ENSP00000467340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251312 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leber congenital amaurosis Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.050	D
MutationAssessor	Benign	1.2	L
PhyloP100		3.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.14	T
Sift4G	Benign	0.39	T
Polyphen		0.016	B
Vest4		0.055
MutPred		0.28		Gain of MoRF binding (P = 0.0667)
MVP		0.98
MPC		0.046
ClinPred		0.17	T
GERP RS		4.0
Varity_R		0.26
gMVP		0.50
Mutation Taster		=22/78	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: rs747653875; hg19: chr1-10042655;