chr11-67629802-G-C

Variant names:

• chr11-67629802-G-C
• rs774719913
• NM_001243750.2:c.110C>G

Variant summary

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

The NM_001243750.2(NUDT8):​c.110C>G​(p.Pro37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,463,634 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. P37Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: NUDT8 NM_001243750.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

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.110C>G	p.Pro37Arg	missense	Exon 1 of 4	NP_001230679.1	Q8WV74-1
	NUDT8	NM_181843.3		c.110C>G	p.Pro37Arg	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.110C>G	p.Pro37Arg	missense	Exon 1 of 4	ENSP00000365883.2	Q8WV74-1
	NUDT8	ENST00000301490.8	TSL:1	c.110C>G	p.Pro37Arg	missense	Exon 1 of 3	ENSP00000301490.4	Q8WV74-2
	NUDT8	ENST00000943310.1		c.110C>G	p.Pro37Arg	missense	Exon 1 of 5	ENSP00000613369.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 33

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: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000234 AC: 3 AN: 128424 AF XY: 0.0000395

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: 0.0000485

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000381 AC: 5 AN: 1311654 Hom.: 0 Cov.: 31 AF XY: 0.00000615 AC XY: 4 AN XY: 650798

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27232

American (AMR) AF: 0.00 AC: 0 AN: 29162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30816

South Asian (SAS) AF: 0.0000148 AC: 1 AN: 67492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3772

European-Non Finnish (NFE) AF: 0.00000384 AC: 4 AN: 1042754

Other (OTH) AF: 0.00 AC: 0 AN: 53142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000494456), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74234

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000358 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.0036	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		2.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.72		Gain of MoRF binding (P = 0.0021)
MVP		0.24
MPC		0.52
ClinPred		0.76	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.65
gMVP		0.40
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs774719913; hg19: chr11-67397273;