chr8-22109276-C-T

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

2
13

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]

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
NUDT18NM_024815.4 linkc.25G>A p.Ala9Thr missense_variant Exon 1 of 3 ENST00000611621.2 NP_079091.3 Q6ZVK8-1
NUDT18XM_011544650.2 linkc.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
NUDT18ENST00000611621.2 linkc.25G>A p.Ala9Thr missense_variant Exon 1 of 3 1 NM_024815.4 ENSP00000480722.1 Q6ZVK8-1
NUDT18ENST00000613958.1 linkc.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.:
0
Cov.:
34
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:
6
AN:
34314
Hom.:
0
AF XY:
0.00
AC XY:
0
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.:
0
Cov.:
32
AF XY:
0.0000820
AC XY:
50
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.:
0
Cov.:
34
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.:
0
Bravo
AF:
0.00137
Asia WGS
AF:
0.000290
AC:
1
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
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.010
T;T
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.42
N
LIST_S2
Benign
0.47
T;T
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.0063
T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.45
T
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
T
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.

Other links and lift over

dbSNP: rs536801022; hg19: chr8-21966789; COSMIC: COSV105864351; COSMIC: COSV105864351; API