chr10-12184892-G-C

Variant names:

• chr10-12184892-G-C
• rs543267377
• NM_014142.4:c.128C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014142.4(NUDT5):​c.128C>G​(p.Thr43Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,379,082 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T43I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NUDT5 NM_014142.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.78
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014142.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT5	NM_014142.4	MANE Select	c.128C>G	p.Thr43Ser	missense	Exon 3 of 10	NP_054861.2
	NUDT5	NM_001321647.2		c.128C>G	p.Thr43Ser	missense	Exon 3 of 9	NP_001308576.1
	NUDT5	NM_001321648.2		c.-226C>G		5_prime_UTR	Exon 3 of 11	NP_001308577.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT5	ENST00000491614.6	TSL:1 MANE Select	c.128C>G	p.Thr43Ser	missense	Exon 3 of 10	ENSP00000419628.1	Q9UKK9
	NUDT5	ENST00000378937.7	TSL:3	c.128C>G	p.Thr43Ser	missense	Exon 3 of 11	ENSP00000368219.3	A6NFX8
	NUDT5	ENST00000905393.1		c.128C>G	p.Thr43Ser	missense	Exon 3 of 10	ENSP00000575452.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000845 AC: 2 AN: 236806 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1379082 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 686590

African (AFR) AF: 0.00 AC: 0 AN: 30638

American (AMR) AF: 0.00 AC: 0 AN: 39980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24078

East Asian (EAS) AF: 0.00 AC: 0 AN: 36088

South Asian (SAS) AF: 0.00 AC: 0 AN: 79190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1056240

Other (OTH) AF: 0.00 AC: 0 AN: 56086

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.072
Sift	Benign	0.32	T
Sift4G	Benign	0.56	T
Polyphen		0.018	B
Vest4		0.23
MutPred		0.26		Gain of phosphorylation at T43 (P = 0.0696)
MVP		0.39
MPC		0.26
ClinPred		0.13	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.34
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 1
DS_DL_spliceai		0.48		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs543267377; hg19: chr10-12226891;