Genetic Variant NADK:p.Ala253Pro (chr1-1757129-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001198994.2(NADK):c.757G>C(p.Ala253Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A253T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

NADK
NM_001198994.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.56

Publications

1 publications found

Variant links:

Genes affected

NADK (HGNC:29831): (NAD kinase) NADK catalyzes the transfer of a phosphate group from ATP to NAD to generate NADP, which in its reduced form acts as an electron donor for biosynthetic reactions (Lerner et al., 2001 [PubMed 11594753]).[supplied by OMIM, Mar 2008]

NADK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.108653605).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198994.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NADK	NM_023018.5	MANE Select	c.393+52G>C		intron	N/A	NP_075394.3
NADK	NM_001198994.2		c.757G>C	p.Ala253Pro	missense	Exon 6 of 14	NP_001185923.1	O95544-2
NADK	NM_001198993.2		c.393+52G>C		intron	N/A	NP_001185922.1	O95544-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NADK	ENST00000378625.5	TSL:1	c.757G>C	p.Ala253Pro	missense	Exon 6 of 14	ENSP00000367890.1	O95544-2
NADK	ENST00000341426.9	TSL:2 MANE Select	c.393+52G>C		intron	N/A	ENSP00000341679.5	O95544-1
NADK	ENST00000341991.7	TSL:1	c.393+52G>C		intron	N/A	ENSP00000344340.3	O95544-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000647

AC:

AN:

154624

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000397

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.20e-7

AC:

AN:

1388692

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31562

American (AMR)

AF:

0.0000277

AC:

AN:

36092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24976

East Asian (EAS)

AF:

0.00

AC:

AN:

35910

South Asian (SAS)

AF:

0.00

AC:

AN:

79068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071930

Other (OTH)

AF:

0.00

AC:

AN:

57520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.30

(source)

DANN

Benign

0.52

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.23

M_CAP

Benign

0.0036

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

PhyloP100

-1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.18

REVEL

Benign

0.041

Sift

Benign

0.11

Sift4G

Benign

0.39

Vest4

0.22

MutPred

0.59

Loss of catalytic residue at A253 (P = 0.0699)

MVP

0.12

ClinPred

0.026

GERP RS

-1.5

PromoterAI

-0.0028

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

gMVP

0.53

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over