chr10-12184911-T-C

Variant names:

• chr10-12184911-T-C
• rs116493013
• NM_014142.4:c.109A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014142.4(NUDT5):​c.109A>G​(p.Met37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,595,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: NUDT5 NM_014142.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.679

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029795647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT5	NM_014142.4	c.109A>G	p.Met37Val	missense_variant	Exon 3 of 10	ENST00000491614.6	NP_054861.2
NUDT5	NM_001321647.2	c.109A>G	p.Met37Val	missense_variant	Exon 3 of 9		NP_001308576.1
NUDT5	NM_001321648.2	c.-245A>G		5_prime_UTR_variant	Exon 3 of 11		NP_001308577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT5	ENST00000491614.6	c.109A>G	p.Met37Val	missense_variant	Exon 3 of 10	1	NM_014142.4	ENSP00000419628.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000203 AC: 5 AN: 246740 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133100

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000554 AC: 80 AN: 1443418 Hom.: 0 Cov.: 26 AF XY: 0.0000459 AC XY: 33 AN XY: 718376

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000228

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: 0.0000519

Gnomad4 OTH exome AF: 0.000201

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.109A>G (p.M37V) alteration is located in exon 3 (coding exon 2) of the NUDT5 gene. This alteration results from a A to G substitution at nucleotide position 109, causing the methionine (M) at amino acid position 37 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	Benign	0.072
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.78
DEOGEN2	Benign	0.23	T;.;T;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.81	.;T;T;T;T;D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.030	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.040	N;.;N;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.25	N;N;N;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.68	T;T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;.
Polyphen		0.0	B;.;B;.;B;.
Vest4		0.083
MVP		0.12
MPC		0.29
ClinPred		0.026	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.40

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: rs116493013; hg19: chr10-12226910;