Variant rs1271498710 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_022787.4(NMNAT1):c.271G>A(p.Glu91Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NMNAT1
NM_022787.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 6.88

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a chain Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (size 278) in uniprot entity NMNA1_HUMAN there are 82 pathogenic changes around while only 2 benign (98%) in NM_022787.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-9975747-G-A is Pathogenic according to our data. Variant chr1-9975747-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438390.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMNAT1	NM_022787.4 linkuse as main transcript	c.271G>A	p.Glu91Lys	missense_variant	3/5	ENST00000377205.6	NP_073624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NMNAT1	ENST00000377205.6 linkuse as main transcript	c.271G>A	p.Glu91Lys	missense_variant	3/5	1	NM_022787.4	ENSP00000366410	P1
NMNAT1	ENST00000403197.5 linkuse as main transcript	c.271G>A	p.Glu91Lys	missense_variant	3/5	2		ENSP00000385131
NMNAT1	ENST00000462686.1 linkuse as main transcript	c.271G>A	p.Glu91Lys	missense_variant, NMD_transcript_variant	3/6	5		ENSP00000435134

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250798

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135576

show subpopulations

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461394

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Leber congenital amaurosis 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 09, 2021

- -

Cone dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Eye Genetics Research Group, Children's Medical Research Institute

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D

Eigen

Benign

-0.022

Eigen_PC

Benign

0.090

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;.

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.2

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

D;N

REVEL

Uncertain

0.51

Sift

Benign

0.27

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.035

.;B

Vest4

0.38

MutPred

0.47

Gain of MoRF binding (P = 0.0063);Gain of MoRF binding (P = 0.0063);

MVP

0.95

MPC

0.052

ClinPred

0.82

GERP RS

4.0

Varity_R

0.34

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over