rs4866

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-2249951-G-A
• chr7-2249951-G-T

Variant summary

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

The NM_198949.2(NUDT1):​c.316G>A​(p.Val106Met) 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.

• Frequency:
  • Genomes: 𝑓 0.018 (57 hom., cov: 33)
  • Exomes 𝑓: 0.014 (418 hom.)
• Consequence: NUDT1 NM_198949.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77
• Publications: 27 publications found

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198949.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT1	NM_002452.4	MANE Select	c.247G>A	p.Val83Met	missense	Exon 3 of 4	NP_002443.3
	NUDT1	NM_198949.2		c.316G>A	p.Val106Met	missense	Exon 4 of 5	NP_945187.1
	NUDT1	NM_198952.2		c.316G>A	p.Val106Met	missense	Exon 4 of 5	NP_945190.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT1	ENST00000356714.6	TSL:1 MANE Select	c.247G>A	p.Val83Met	missense	Exon 3 of 4	ENSP00000349148.1
	NUDT1	ENST00000343985.8	TSL:1	c.316G>A	p.Val106Met	missense	Exon 3 of 4	ENSP00000339503.4
	NUDT1	ENST00000397048.5	TSL:1	c.316G>A	p.Val106Met	missense	Exon 4 of 5	ENSP00000380241.1

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

African (AFR) AF: 0.0181 AC: 605 AN: 33480

American (AMR) AF: 0.00637 AC: 285 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 1517 AN: 26136

East Asian (EAS) AF: 0.0694 AC: 2754 AN: 39700

South Asian (SAS) AF: 0.0282 AC: 2434 AN: 86258

European-Finnish (FIN) AF: 0.0627 AC: 3347 AN: 53370

Middle Eastern (MID) AF: 0.0336 AC: 194 AN: 5768

European-Non Finnish (NFE) AF: 0.00698 AC: 7766 AN: 1112002

Other (OTH) 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

African (AFR) AF: 0.0155 AC: 646 AN: 41576

American (AMR) AF: 0.0114 AC: 174 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3472

East Asian (EAS) AF: 0.0407 AC: 211 AN: 5180

South Asian (SAS) AF: 0.0281 AC: 136 AN: 4834

European-Finnish (FIN) AF: 0.0706 AC: 750 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00944 AC: 642 AN: 68030

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
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
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.019	D
Sift4G	Benign	0.095	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

Other links and lift over

dbSNP: rs4866; hg19: chr7-2289586; COSMIC: COSV56126959; COSMIC: COSV56126959;