10-12172829-T-C

Position:

• chr10-12172829-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014142.4(NUDT5):​c.423A>G​(p.Ile141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUDT5 NM_014142.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.28

Genes affected

NUDT5 (HGNC:8052): (nudix hydrolase 5) This gene belongs to the Nudix (nucleoside diphosphate linked moiety X) hydrolase superfamily. The encoded enzyme catalyzes the hydrolysis of modified nucleoside diphosphates, including ADP-ribose (ADPR) and 8-oxoGua-containing 8-oxo-dADP and 8-oxo-dGDP. Protein-bound ADP ribose can be hazardous to the cell because it can modify some amino acid residues, resulting in the inhibition of ATP-activated potassium channels. 8-oxoGua is an oxidized form of guanine that can potentially alter genetic information by pairing with adenine and cytosine in RNA. Presence of 8-oxoGua in RNA results in formation of abnormal proteins due to translational errors. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13317761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUDT5	NM_014142.4	c.423A>G	p.Ile141Met	missense_variant	7/10	ENST00000491614.6	NP_054861.2
NUDT5	NM_001321647.2	c.423A>G	p.Ile141Met	missense_variant	7/9		NP_001308576.1
NUDT5	NM_001321648.2	c.165A>G	p.Ile55Met	missense_variant	8/11		NP_001308577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUDT5	ENST00000491614.6	c.423A>G	p.Ile141Met	missense_variant	7/10	1	NM_014142.4	ENSP00000419628.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Apr 15, 2024

The c.423A>G (p.I141M) alteration is located in exon 7 (coding exon 6) of the NUDT5 gene. This alteration results from a A to G substitution at nucleotide position 423, causing the isoleucine (I) at amino acid position 141 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;.;T;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.67	.;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N;.;N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.99	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.67	P;.;P;.;P
Vest4		0.28
MutPred		0.49		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.49
MPC		0.30
ClinPred		0.16	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.18
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-12214828;