chr1-1754137-T-G

Variant names:

• chr1-1754137-T-G
• rs566351993
• NM_023018.5:c.1015A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_023018.5(NADK):​c.1015A>C​(p.Asn339His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,611,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N339N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (1 hom.)
• Consequence: NADK NM_023018.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39778748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NADK	NM_023018.5	c.1015A>C	p.Asn339His	missense_variant	Exon 10 of 12	ENST00000341426.9	NP_075394.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NADK	ENST00000341426.9	c.1015A>C	p.Asn339His	missense_variant	Exon 10 of 12	2	NM_023018.5	ENSP00000341679.5

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000684 AC: 17 AN: 248466 AF XY: 0.0000816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000486 AC: 71 AN: 1459738 Hom.: 1 Cov.: 33 AF XY: 0.0000689 AC XY: 50 AN XY: 726168

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52520

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111450

Other (OTH) AF: 0.0000332 AC: 2 AN: 60318

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41524

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1450A>C (p.N484H) alteration is located in exon 12 (coding exon 11) of the NADK gene. This alteration results from a A to C substitution at nucleotide position 1450, causing the asparagine (N) at amino acid position 484 to be replaced by a histidine (H). 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	0.33
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.8	L;L;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.88
MutPred		0.40		Loss of catalytic residue at N339 (P = 0.0624);Loss of catalytic residue at N339 (P = 0.0624);.;.;
MVP		0.59
ClinPred		0.46	T
GERP RS		4.1
Varity_R		0.87
gMVP		0.80
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs566351993; hg19: chr1-1685576;