11-67629766-T-C

Variant names:

• chr11-67629766-T-C
• rs769159278
• NM_001243750.2:c.146A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001243750.2(NUDT8):​c.146A>G​(p.Tyr49Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,389,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y49S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NUDT8 NM_001243750.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.322
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243750.2. 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
	NUDT8	NM_001243750.2	MANE Select	c.146A>G	p.Tyr49Cys	missense	Exon 1 of 4	NP_001230679.1	Q8WV74-1
	NUDT8	NM_181843.3		c.146A>G	p.Tyr49Cys	missense	Exon 1 of 3	NP_862826.1	Q8WV74-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUDT8	ENST00000376693.3	TSL:2 MANE Select	c.146A>G	p.Tyr49Cys	missense	Exon 1 of 4	ENSP00000365883.2	Q8WV74-1
	NUDT8	ENST00000301490.8	TSL:1	c.146A>G	p.Tyr49Cys	missense	Exon 1 of 3	ENSP00000301490.4	Q8WV74-2
	NUDT8	ENST00000943310.1		c.146A>G	p.Tyr49Cys	missense	Exon 1 of 5	ENSP00000613369.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000604 AC: 1 AN: 165464 AF XY: 0.0000105

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: 0.0000841

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1389234 Hom.: 0 Cov.: 30 AF XY: 0.00000289 AC XY: 2 AN XY: 691308

African (AFR) AF: 0.00 AC: 0 AN: 28754

American (AMR) AF: 0.00 AC: 0 AN: 37706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24366

East Asian (EAS) AF: 0.00 AC: 0 AN: 32340

South Asian (SAS) AF: 0.00 AC: 0 AN: 80362

European-Finnish (FIN) AF: 0.0000990 AC: 4 AN: 40422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084060

Other (OTH) AF: 0.00 AC: 0 AN: 57100

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000174 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.17	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.32
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.68		Gain of disorder (P = 0.0122)
MVP		0.19
MPC		1.0
ClinPred		0.96	D
GERP RS		2.9
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.73
gMVP		0.26
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs769159278; hg19: chr11-67397237;