Genetic Variant NAPRT:c.226+74T>A (chr8-143578019-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145201.6(NAPRT):c.226+74T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,521,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

NAPRT
NM_145201.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.01

Publications

10 publications found

Variant links:

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]

NAPRT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145201.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NAPRT	NM_145201.6	MANE Select	c.226+74T>A	intron	N/A	NP_660202.3
NAPRT	NM_001286829.2		c.226+74T>A	intron	N/A	NP_001273758.1	Q6XQN6-3
NAPRT	NM_001363145.1		c.226+74T>A	intron	N/A	NP_001350074.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NAPRT	ENST00000449291.7	TSL:1 MANE Select	c.226+74T>A	intron	N/A	ENSP00000401508.2	Q6XQN6-1
NAPRT	ENST00000426292.7	TSL:1	c.226+74T>A	intron	N/A	ENSP00000390949.3	Q6XQN6-3
NAPRT	ENST00000340490.7	TSL:1	n.226+74T>A	intron	N/A	ENSP00000341136.3	G5E977

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

150244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000979

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1371562

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

675986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30848

American (AMR)

AF:

0.00

AC:

AN:

37312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21854

East Asian (EAS)

AF:

0.00

AC:

AN:

37904

South Asian (SAS)

AF:

0.00

AC:

AN:

77264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4694

European-Non Finnish (NFE)

AF:

0.0000433

AC:

AN:

1063180

Other (OTH)

AF:

0.00

AC:

AN:

56674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

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:

0.0000266

AC:

AN:

150244

Hom.:

Cov.:

AF XY:

0.0000546

AC XY:

AN XY:

73296

show subpopulations

African (AFR)

AF:

0.0000979

AC:

AN:

40862

American (AMR)

AF:

0.00

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5038

South Asian (SAS)

AF:

0.00

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67390

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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:

0.00

Hom.:

1626

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.1

(source)

DANN

Benign

0.27

PhyloP100

-4.0

BranchPoint Hunter

0.0

PromoterAI

-0.030

Neutral

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over