9-34343285-G-C

Position:

• chr9-34343285-G-C

Variant summary

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

The NM_001161.5(NUDT2):​c.289G>C​(p.Glu97Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,842 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: 6.9e-7 (0 hom.)
• Consequence: NUDT2 NM_001161.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.73

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, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT2	NM_001161.5	c.289G>C	p.Glu97Gln	missense_variant	5/5	ENST00000379158.7	NP_001152.1
NUDT2	NM_001244390.2	c.289G>C	p.Glu97Gln	missense_variant	3/3		NP_001231319.1
NUDT2	NM_147172.3	c.289G>C	p.Glu97Gln	missense_variant	5/5		NP_671701.1
NUDT2	NM_147173.3	c.289G>C	p.Glu97Gln	missense_variant	4/4		NP_671702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUDT2	ENST00000379158.7	c.289G>C	p.Glu97Gln	missense_variant	5/5	3	NM_001161.5	ENSP00000368455.1
NUDT2	ENST00000346365.8	c.289G>C	p.Glu97Gln	missense_variant	4/4	1		ENSP00000344187.4
NUDT2	ENST00000379155.9	c.289G>C	p.Glu97Gln	missense_variant	5/5	3		ENSP00000368452.5
NUDT2	ENST00000618590.1	c.289G>C	p.Glu97Gln	missense_variant	3/3	3		ENSP00000482384.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2023

The c.289G>C (p.E97Q) alteration is located in exon 5 (coding exon 2) of the NUDT2 gene. This alteration results from a G to C substitution at nucleotide position 289, causing the glutamic acid (E) at amino acid position 97 to be replaced by a glutamine (Q). 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	0.16
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;.
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Benign	0.25
Sift	Uncertain	0.018	D;D;.;D
Sift4G	Uncertain	0.033	D;D;D;D
Polyphen		0.73	P;P;P;P
Vest4		0.79
MutPred		0.61		Gain of MoRF binding (P = 0.03);Gain of MoRF binding (P = 0.03);Gain of MoRF binding (P = 0.03);Gain of MoRF binding (P = 0.03);
MVP		0.53
MPC		1.4
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.46
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs942774729; hg19: chr9-34343283;