1-1756523-T-C

Variant names:

• chr1-1756523-T-C
• rs771146301
• NM_023018.5:c.479A>G

Variant summary

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

The NM_023018.5(NADK):​c.479A>G​(p.Lys160Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000062 (0 hom.)
• Consequence: NADK NM_023018.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

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]

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=0.14025855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NADK	NM_023018.5	c.479A>G	p.Lys160Arg	missense_variant	Exon 5 of 12	ENST00000341426.9	NP_075394.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NADK	ENST00000341426.9	c.479A>G	p.Lys160Arg	missense_variant	Exon 5 of 12	2	NM_023018.5	ENSP00000341679.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251160 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461748 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

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

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.914A>G (p.K305R) alteration is located in exon 7 (coding exon 6) of the NADK gene. This alteration results from a A to G substitution at nucleotide position 914, causing the lysine (K) at amino acid position 305 to be replaced by an arginine (R). 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	0.064
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T;T;.;T
Eigen	Benign	-0.046
Eigen_PC	Benign	0.095
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.54	N;N;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.093
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.029	B;B;.;.
Vest4		0.19
MutPred		0.52		Loss of methylation at K160 (P = 0.0307);Loss of methylation at K160 (P = 0.0307);.;.;
MVP		0.54
ClinPred		0.16	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.44

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: rs771146301; hg19: chr1-1687962;