chr9-34343283-C-T

Variant names:

• chr9-34343283-C-T
• rs200364521
• NM_001161.5:c.287C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001161.5(NUDT2):​c.287C>T​(p.Ala96Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,459,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: NUDT2 NM_001161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

Genes affected

NUDT2 (HGNC:8049): (nudix hydrolase 2) This gene encodes a member of the MutT family of nucleotide pyrophosphatases, a subset of the larger NUDIX hydrolase family. The gene product possesses a modification of the MutT sequence motif found in certain nucleotide pyrophosphatases. The enzyme asymmetrically hydrolyzes Ap4A to yield AMP and ATP and is responsible for maintaining the intracellular level of the dinucleotide Ap4A, the function of which has yet to be established. This gene may be a candidate tumor suppressor gene. Alternative splicing has been observed at this locus and four transcript variants, all encoding the same protein, have been identified. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT2	NM_001161.5	c.287C>T	p.Ala96Val	missense_variant	Exon 5 of 5	ENST00000379158.7	NP_001152.1
NUDT2	NM_001244390.2	c.287C>T	p.Ala96Val	missense_variant	Exon 3 of 3		NP_001231319.1
NUDT2	NM_147172.3	c.287C>T	p.Ala96Val	missense_variant	Exon 5 of 5		NP_671701.1
NUDT2	NM_147173.3	c.287C>T	p.Ala96Val	missense_variant	Exon 4 of 4		NP_671702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT2	ENST00000379158.7	c.287C>T	p.Ala96Val	missense_variant	Exon 5 of 5	3	NM_001161.5	ENSP00000368455.1
NUDT2	ENST00000346365.8	c.287C>T	p.Ala96Val	missense_variant	Exon 4 of 4	1		ENSP00000344187.4
NUDT2	ENST00000379155.9	c.287C>T	p.Ala96Val	missense_variant	Exon 5 of 5	3		ENSP00000368452.5
NUDT2	ENST00000618590.1	c.287C>T	p.Ala96Val	missense_variant	Exon 3 of 3	3		ENSP00000482384.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000206 AC: 5 AN: 243112 Hom.: 0 AF XY: 0.0000226 AC XY: 3 AN XY: 132998

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1459026 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725798

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.287C>T (p.A96V) alteration is located in exon 5 (coding exon 2) of the NUDT2 gene. This alteration results from a C to T substitution at nucleotide position 287, causing the alanine (A) at amino acid position 96 to be replaced by a valine (V). 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.059	T;T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;.
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M;M;M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.82
MutPred		0.75		Loss of ubiquitination at K99 (P = 0.1264);Loss of ubiquitination at K99 (P = 0.1264);Loss of ubiquitination at K99 (P = 0.1264);Loss of ubiquitination at K99 (P = 0.1264);
MVP		0.38
MPC		1.3
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.71
gMVP		0.78

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: rs200364521; hg19: chr9-34343281; COSMIC: COSV104414875;