10-12177821-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001321648.2(NUDT5):c.3G>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

NUDT5
NM_001321648.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56

Variant links:

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]

NUDT5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 46 codons. Genomic position: 12172858. Lost 0.338 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT5	NM_014142.4 link	c.261G>C	p.Met87Ile	missense_variant	Exon 5 of 10	ENST00000491614.6	NP_054861.2	Q9UKK9
NUDT5	NM_001321648.2 link	c.3G>C	p.Met1?	start_lost	Exon 6 of 11		NP_001308577.1
NUDT5	NM_001321647.2 link	c.261G>C	p.Met87Ile	missense_variant	Exon 5 of 9		NP_001308576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT5	ENST00000491614.6 link	c.261G>C	p.Met87Ile	missense_variant	Exon 5 of 10	1	NM_014142.4	ENSP00000419628.1		Q9UKK9

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000255

AC:

AN:

251422

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000286

AC:

418

AN:

1461774

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

223

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000243

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000375

Hom.:

Bravo

AF:

0.000230

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000272

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.261G>C (p.M87I) alteration is located in exon 5 (coding exon 4) of the NUDT5 gene. This alteration results from a G to C substitution at nucleotide position 261, causing the methionine (M) at amino acid position 87 to be replaced by an isoleucine (I). 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.20

T;.;T;.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

.;T;T;T;D

M_CAP

Benign

0.0057

MetaRNN

Benign

0.028

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.62

N;.;N;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.080

N;N;N;N;N

REVEL

Benign

0.040

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.90

T;T;T;T;T

Polyphen

0.0010

B;.;B;.;B

Vest4

0.29

MutPred

0.46

Gain of catalytic residue at M87 (P = 0.1814);.;Gain of catalytic residue at M87 (P = 0.1814);Gain of catalytic residue at M87 (P = 0.1814);Gain of catalytic residue at M87 (P = 0.1814);

MVP

0.48

MPC

0.32

ClinPred

0.014

GERP RS

2.9

Varity_R

0.15

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over