dbSNP rs138613460: NMNAT1:p.Ala13Thr (chr1-9972110-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PS3PM1PM5PP2PP3PP5BP4

The NM_022787.4(NMNAT1):c.37G>A(p.Ala13Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,612,714 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002008744: "In a published functional study, this variant performed similar to wildtype, however additional studies are needed to validate the functional effect of this variant in vivo." PMID:26018082". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

NMNAT1
NM_022787.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:4

Conservation

PhyloP100: 9.56

Publications

6 publications found

Variant links:

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)

NMNAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002008744: "In a published functional study, this variant performed similar to wildtype, however additional studies are needed to validate the functional effect of this variant in vivo." PMID: 26018082

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_022787.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-9972111-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1376825.Status of the report is criteria_provided_single_submitter, 1 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 spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, cone-rod dystrophy, NMNAT1-related retinopathy, Leber congenital amaurosis 9, Leber congenital amaurosis.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 1-9972110-G-A is Pathogenic according to our data. Variant chr1-9972110-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195375.

BP4

Computational evidence support a benign effect (MetaRNN=0.18942168). . 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NMNAT1	NM_022787.4	MANE Select	c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	NP_073624.2
NMNAT1	NM_001297778.1		c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	NP_001284707.1	Q9HAN9
NMNAT1	NM_001297779.2		c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	NP_001284708.1	B1AN62

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NMNAT1	ENST00000377205.6	TSL:1 MANE Select	c.37G>A	p.Ala13Thr	missense	Exon 2 of 5	ENSP00000366410.1	Q9HAN9
NMNAT1	ENST00000887500.1		c.37G>A	p.Ala13Thr	missense	Exon 3 of 6	ENSP00000557559.1
NMNAT1	ENST00000946962.1		c.37G>A	p.Ala13Thr	missense	Exon 3 of 6	ENSP00000617021.1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

251108

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000630

AC:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726640

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

33444

American (AMR)

AF:

0.000157

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110828

Other (OTH)

AF:

0.0000663

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000539

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

41536

American (AMR)

AF:

0.000131

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000783

Hom.:

Bravo

AF:

0.000555

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leber congenital amaurosis 9 (6)

not provided (3)

Retinal dystrophy (2)

NMNAT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.19

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

PhyloP100

9.6

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.87

MVP

0.98

MPC

0.30

ClinPred

0.25

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.84

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over