rs147220828

Positions:

• chr1-9982688-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM2 BP4_Strong BP6_Moderate

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a chain Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (size 278) in uniprot entity NMNA1_HUMAN there are 122 pathogenic changes around while only 6 benign (95%) in NM_022787.4
• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_benign]. Clinvar id is 464671.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMNAT1	NM_022787.4	c.827A>C	p.Glu276Ala	missense_variant	5/5	ENST00000377205.6	NP_073624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NMNAT1	ENST00000377205.6	c.827A>C	p.Glu276Ala	missense_variant	5/5	1	NM_022787.4	ENSP00000366410.1
NMNAT1	ENST00000496751.1	c.118+1518A>C		intron_variant		2		ENSP00000467340.1
NMNAT1	ENST00000462686.1	n.827A>C		non_coding_transcript_exon_variant	5/6	5		ENSP00000435134.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152226 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000181 AC: 44 AN: 242660 Hom.: 0 AF XY: 0.0000911 AC XY: 12 AN XY: 131734

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 SAS 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.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 78 AN XY: 721946

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.000139

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: 0.0000406

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74494

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0230 Hom.: 2351

Bravo AF: 0.00105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00300 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	5.1
DANN	Benign	0.94
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.77	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.10	T
Sift4G	Benign	0.23	T
Polyphen		0.0030	B
Vest4		0.13
MVP		0.89
MPC		0.054
ClinPred		0.0057	T
GERP RS		2.6
Varity_R		0.050
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs147220828; hg19: chr1-10042746;