rs147220828

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_022787.4(NMNAT1):c.827A>C(p.Glu276Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,605,146 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E276V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

NMNAT1
NM_022787.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.14

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.008302271).

BP6

Variant 1-9982688-A-C is Benign according to our data. Variant chr1-9982688-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464671.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT1	NM_022787.4 link	c.827A>C	p.Glu276Ala	missense_variant	Exon 5 of 5	ENST00000377205.6	NP_073624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NMNAT1	ENST00000377205.6 link	c.827A>C	p.Glu276Ala	missense_variant	Exon 5 of 5	1	NM_022787.4	ENSP00000366410.1
NMNAT1	ENST00000462686.1 link	n.827A>C		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000435134.1
NMNAT1	ENST00000496751.1 link	c.118+1518A>C		intron_variant	Intron 1 of 1	2		ENSP00000467340.1

Frequencies

GnomAD3 genomes

AF:

0.000933

AC:

142

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000181

AC:

AN:

242660

AF XY:

0.0000911

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.0000914

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000272

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1452802

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

721946

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33090

American (AMR)

AF:

0.000139

AC:

AN:

43050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25618

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

85158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000406

AC:

AN:

1107372

Other (OTH)

AF:

0.000200

AC:

AN:

59950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000932

AC:

142

AN:

152344

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41584

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0199

Hom.:

2351

Bravo

AF:

0.00105

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00300

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leber congenital amaurosis 9;C5543257:Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Leber congenital amaurosis 9

Benign:1

Oct 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.20

CADD

Benign

5.1

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.021

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.16

M_CAP

Benign

0.042

MetaRNN

Benign

0.0083

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.77

PhyloP100

1.1

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

REVEL

Benign

0.23

Sift

Benign

0.10

Sift4G

Benign

0.23

Polyphen

0.0030

Vest4

0.13

MVP

0.89

MPC

0.054

ClinPred

0.0057

GERP RS

2.6

Varity_R

0.050

gMVP

0.55

Mutation Taster

=98/2

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over