Genetic Variant NUDT8:p.Tyr49Ser (chr11-67629766-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001243750.2(NUDT8):c.146A>C(p.Tyr49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000843 in 1,541,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

NUDT8
NM_001243750.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.322

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]

NUDT8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT8	NM_001243750.2 link	c.146A>C	p.Tyr49Ser	missense_variant	Exon 1 of 4	ENST00000376693.3	NP_001230679.1	Q8WV74-1
NUDT8	NM_181843.3 link	c.146A>C	p.Tyr49Ser	missense_variant	Exon 1 of 3		NP_862826.1	Q8WV74-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NUDT8	ENST00000376693.3 link	c.146A>C	p.Tyr49Ser	missense_variant	Exon 1 of 4	2	NM_001243750.2	ENSP00000365883.2	Q8WV74-1
NUDT8	ENST00000301490.8 link	c.146A>C	p.Tyr49Ser	missense_variant	Exon 1 of 3	1		ENSP00000301490.4	Q8WV74-2
NUDT8	ENST00000534054.1 link	n.156A>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

165464

Hom.:

AF XY:

0.0000105

AC XY:

AN XY:

95236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000382

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:

0.0000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000720

AC:

AN:

1389234

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691308

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000530

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:

0.00000738

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000869

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146A>C (p.Y49S) alteration is located in exon 1 (coding exon 1) of the NUDT8 gene. This alteration results from a A to C substitution at nucleotide position 146, causing the tyrosine (Y) at amino acid position 49 to be replaced by a serine (S). 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

0.96

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.076

.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.0095

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.95

P;P

Vest4

0.53

MutPred

0.70

Gain of disorder (P = 4e-04);Gain of disorder (P = 4e-04);

MVP

0.11

MPC

0.73

ClinPred

0.95

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.79

gMVP

0.41

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