8-143575450-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145201.6(NAPRT):c.1264G>A(p.Ala422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,441,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NAPRT NM_145201.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.963

Genes affected

NAPRT (HGNC:30450): (nicotinate phosphoribosyltransferase) Nicotinic acid (NA; niacin) is converted by nicotinic acid phosphoribosyltransferase (NAPRT; EC 2.4.2.11) to NA mononucleotide (NaMN), which is then converted to NA adenine dinucleotide (NaAD), and finally to nicotinamide adenine dinucleotide (NAD), which serves as a coenzyme in cellular redox reactions and is an essential component of a variety of processes in cellular metabolism including response to stress (Hara et al., 2007).[supplied by OMIM, Mar 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12414661).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAPRT	NM_145201.6	c.1264G>A	p.Ala422Thr	missense_variant	10/13	ENST00000449291.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAPRT	ENST00000449291.7	c.1264G>A	p.Ala422Thr	missense_variant	10/13	1	NM_145201.6	P1
	ENST00000531730.1	n.436+344C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 250026 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135400

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.0000532

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000173 AC: 25 AN: 1441678 Hom.: 0 Cov.: 36 AF XY: 0.0000182 AC XY: 13 AN XY: 712428

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000901

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: 0.0000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.1264G>A (p.A422T) alteration is located in exon 10 (coding exon 10) of the NAPRT gene. This alteration results from a G to A substitution at nucleotide position 1264, causing the alanine (A) at amino acid position 422 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0081	T;T;.
Eigen	Benign	-0.085
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	T;.;.
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.050	N;N;N
REVEL	Benign	0.079
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.98	D;B;B
Vest4		0.13
MutPred		0.32		Gain of phosphorylation at A422 (P = 0.0206);Gain of phosphorylation at A422 (P = 0.0206);Gain of phosphorylation at A422 (P = 0.0206);
MVP		0.35
MPC		0.14
ClinPred		0.16	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.38

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: rs568720796; hg19: chr8-144657620;