chr11-67628995-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001243750.2(NUDT8):​c.251G>A​(p.Arg84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NUDT8
NM_001243750.2 missense

Scores

11
4
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17
Variant links:
Genes affected
NUDT8 (HGNC:8055): (nudix hydrolase 8) Predicted to enable magnesium ion binding activity and manganese ion binding activity. Predicted to be involved in purine nucleoside bisphosphate catabolic process. Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NUDT8NM_001243750.2 linkc.251G>A p.Arg84Gln missense_variant Exon 2 of 4 ENST00000376693.3 NP_001230679.1 Q8WV74-1
NUDT8NM_181843.3 linkc.251G>A p.Arg84Gln missense_variant Exon 2 of 3 NP_862826.1 Q8WV74-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NUDT8ENST00000376693.3 linkc.251G>A p.Arg84Gln missense_variant Exon 2 of 4 2 NM_001243750.2 ENSP00000365883.2 Q8WV74-1
NUDT8ENST00000301490.8 linkc.251G>A p.Arg84Gln missense_variant Exon 2 of 3 1 ENSP00000301490.4 Q8WV74-2
NUDT8ENST00000534054.1 linkn.927G>A non_coding_transcript_exon_variant Exon 1 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152258
Hom.:
0
Cov.:
33
show subpopulations
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
250080
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135548
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000444
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1460644
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
726612
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74390
show subpopulations
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 06, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.251G>A (p.R84Q) alteration is located in exon 2 (coding exon 2) of the NUDT8 gene. This alteration results from a G to A substitution at nucleotide position 251, causing the arginine (R) at amino acid position 84 to be replaced by a glutamine (Q). 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
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
.;T
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Benign
0.66
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Benign
0.073
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.073
D
MutationAssessor
Pathogenic
4.6
H;H
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.89
Loss of phosphorylation at T86 (P = 0.0909);Loss of phosphorylation at T86 (P = 0.0909);
MVP
0.61
MPC
1.0
ClinPred
1.0
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.76
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs777325380; hg19: chr11-67396466; API