7-2249951-G-A

Variant names:

• chr7-2249951-G-A
• rs4866
• NM_002452.4:c.247G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002452.4(NUDT1):​c.247G>A​(p.Val83Met) variant causes a missense change. The variant allele was found at a frequency of 0.0141 in 1,614,176 control chromosomes in the GnomAD database, including 475 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (57 hom., cov: 33)
  • Exomes 𝑓: 0.014 (418 hom.)
• Consequence: NUDT1 NM_002452.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77

Genes affected

NUDT1 (HGNC:8048): (nudix hydrolase 1) Misincorporation of oxidized nucleoside triphosphates into DNA/RNA during replication and transcription can cause mutations that may result in carcinogenesis or neurodegeneration. The protein encoded by this gene is an enzyme that hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP, to monophosphates, thereby preventing misincorporation. The encoded protein is localized mainly in the cytoplasm, with some in the mitochondria, suggesting that it is involved in the sanitization of nucleotide pools both for nuclear and mitochondrial genomes. Several alternatively spliced transcript variants, some of which encode distinct isoforms, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A rare single-nucleotide polymorphism that results in the production of an additional, longer isoform (p26) has been described. [provided by RefSeq, Dec 2018]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068998635).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT1	NM_002452.4	c.247G>A	p.Val83Met	missense_variant	Exon 3 of 4	ENST00000356714.6	NP_002443.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT1	ENST00000356714.6	c.247G>A	p.Val83Met	missense_variant	Exon 3 of 4	1	NM_002452.4	ENSP00000349148.1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2776 AN: 152226 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0406

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0215 AC: 5408 AN: 251386 AF XY: 0.0222

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.00604

Gnomad ASJ exome AF: 0.0586

Gnomad EAS exome AF: 0.0359

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0137 AC: 19999 AN: 1461832 Hom.: 418 Cov.: 31 AF XY: 0.0144 AC XY: 10507 AN XY: 727210

Gnomad4 AFR exome AF: 0.0181 AC: 605 AN: 33480

Gnomad4 AMR exome AF: 0.00637 AC: 285 AN: 44724

Gnomad4 ASJ exome AF: 0.0580 AC: 1517 AN: 26136

Gnomad4 EAS exome AF: 0.0694 AC: 2754 AN: 39700

Gnomad4 SAS exome AF: 0.0282 AC: 2434 AN: 86258

Gnomad4 FIN exome AF: 0.0627 AC: 3347 AN: 53370

Gnomad4 NFE exome AF: 0.00698 AC: 7766 AN: 1112002

Gnomad4 Remaining exome AF: 0.0182 AC: 1097 AN: 60394

GnomAD4 genome AF: 0.0183 AC: 2782 AN: 152344 Hom.: 57 Cov.: 33 AF XY: 0.0216 AC XY: 1609 AN XY: 74490

Gnomad4 AFR AF: 0.0155 AC: 0.0155378 AN: 0.0155378

Gnomad4 AMR AF: 0.0114 AC: 0.0113651 AN: 0.0113651

Gnomad4 ASJ AF: 0.0513 AC: 0.0512673 AN: 0.0512673

Gnomad4 EAS AF: 0.0407 AC: 0.0407336 AN: 0.0407336

Gnomad4 SAS AF: 0.0281 AC: 0.0281341 AN: 0.0281341

Gnomad4 FIN AF: 0.0706 AC: 0.0706082 AN: 0.0706082

Gnomad4 NFE AF: 0.00944 AC: 0.00943701 AN: 0.00943701

Gnomad4 OTH AF: 0.0208 AC: 0.0208136 AN: 0.0208136

Alfa AF: 0.0132 Hom.: 104

Bravo AF: 0.0140

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.0206 AC: 2499

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.0138

EpiControl AF: 0.0145

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;.;.;T;.;T
MetaRNN	Benign	0.0069	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;.
REVEL	Benign	0.26
Sift	Uncertain	0.019	D;D;T;T;D;.
Sift4G	Benign	0.095	T;T;T;T;T;T
Vest4		0.12
MPC		0.16
ClinPred		0.011	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.78
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4866; hg19: chr7-2289586; COSMIC: COSV56126959; COSMIC: COSV56126959;