Genetic Variant NUDT5:p.Met87Ile (chr10-12177821-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

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

The NM_001321648.2(NUDT5):c.3G>T(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 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NUDT5
NM_001321648.2 start_lost

Scores

Clinical Significance

Not reported in ClinVar

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:

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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>T	p.Met87Ile	missense_variant	Exon 5 of 10	ENST00000491614.6	NP_054861.2	Q9UKK9
NUDT5	NM_001321648.2 link	c.3G>T	p.Met1?	start_lost	Exon 6 of 11		NP_001308577.1
NUDT5	NM_001321647.2 link	c.261G>T	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>T	p.Met87Ile	missense_variant	Exon 5 of 10	1	NM_014142.4	ENSP00000419628.1		Q9UKK9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727192

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.20

T;.;T;.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

.;T;T;T;D

M_CAP

Benign

0.0058

MetaRNN

Benign

0.091

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

0.037

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

0.41

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over