Genetic Variant NUDT18:p.Ala9Thr (chr8-22109276-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024815.4(NUDT18):c.25G>A(p.Ala9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,396,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

NUDT18
NM_024815.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.530

Variant links:

Genes affected

NUDT18 (HGNC:26194): (nudix hydrolase 18) The protein encoded by this gene is a member of the Nudix hydrolase family. Nudix hydrolases eliminate potentially toxic nucleotide metabolites from the cell and regulate the concentrations and availability of many different nucleotide substrates, cofactors, and signaling molecules. This protein contains a Nudix hydrolase domain and hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates. [provided by RefSeq, Sep 2012]

NUDT18 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.0063221455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT18	NM_024815.4 link	c.25G>A	p.Ala9Thr	missense_variant	Exon 1 of 3	ENST00000611621.2	NP_079091.3	Q6ZVK8-1
NUDT18	XM_011544650.2 link	c.673G>A	p.Ala225Thr	missense_variant	Exon 2 of 4		XP_011542952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT18	ENST00000611621.2 link	c.25G>A	p.Ala9Thr	missense_variant	Exon 1 of 3	1	NM_024815.4	ENSP00000480722.1		Q6ZVK8-1
NUDT18	ENST00000613958.1 link	c.25G>A	p.Ala9Thr	missense_variant	Exon 1 of 2	2		ENSP00000479883.1		A0A087WW30

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

211

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00481

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000175

AC:

AN:

34314

Hom.:

AF XY:

0.00

AC XY:

AN XY:

21226

show subpopulations

Gnomad AFR exome

AF:

0.0127

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

128

AN:

1244652

Hom.:

Cov.:

AF XY:

0.0000820

AC XY:

AN XY:

609906

show subpopulations

Gnomad4 AFR exome

AF:

0.00441

Gnomad4 AMR exome

AF:

0.000331

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.87e-7

Gnomad4 OTH exome

AF:

0.000235

GnomAD4 genome

AF:

0.00139

AC:

211

AN:

151980

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00480

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:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000713

Hom.:

Bravo

AF:

0.00137

Asia WGS

AF:

0.000290

AC:

AN:

3460

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.25G>A (p.A9T) alteration is located in exon 1 (coding exon 1) of the NUDT18 gene. This alteration results from a G to A substitution at nucleotide position 25, causing the alanine (A) at amino acid position 9 to be replaced by a threonine (T). 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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.010

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.47

T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.45

Sift4G

Benign

0.19

T;T

Polyphen

0.0010

B;.

Vest4

0.030

MutPred

0.33

Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);

MVP

0.095

ClinPred

0.033

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.039

gMVP

0.34

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