Genetic Variant NUDT12:p.Pro323Gln (chr5-103554850-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_031438.4(NUDT12):c.968C>A(p.Pro323Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,116 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. P323L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

NUDT12
NM_031438.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.54

Publications

0 publications found

Variant links:

Genes affected

NUDT12 (HGNC:18826): (nudix hydrolase 12) Nucleotides are involved in numerous biochemical reactions and pathways within the cell as substrates, cofactors, and effectors. Nudix hydrolases, such as NUDT12, regulate the concentrations of individual nucleotides and of nucleotide ratios in response to changing circumstances (Abdelraheim et al., 2003 [PubMed 12790796]).[supplied by OMIM, Mar 2008]

NUDT12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4 link	c.968C>A	p.Pro323Gln	missense_variant	Exon 5 of 7	ENST00000230792.7	NP_113626.1	Q9BQG2-1
NUDT12	NM_001300741.2 link	c.914C>A	p.Pro305Gln	missense_variant	Exon 5 of 7		NP_001287670.1	Q9BQG2-2
NUDT12	XM_005272095.2 link	c.968C>A	p.Pro323Gln	missense_variant	Exon 5 of 7		XP_005272152.1	Q9BQG2-1
NUDT12	XM_005272097.4 link	c.914C>A	p.Pro305Gln	missense_variant	Exon 5 of 7		XP_005272154.1	Q9BQG2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NUDT12	ENST00000230792.7 link	c.968C>A	p.Pro323Gln	missense_variant	Exon 5 of 7	1	NM_031438.4	ENSP00000230792.2	Q9BQG2-1
NUDT12	ENST00000507423.1 link	c.914C>A	p.Pro305Gln	missense_variant	Exon 5 of 7	2		ENSP00000424521.1	Q9BQG2-2
NUDT12	ENST00000515407.1 link	n.163C>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1305116

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

653270

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27690

American (AMR)

AF:

0.00

AC:

AN:

34336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23208

East Asian (EAS)

AF:

0.00

AC:

AN:

36066

South Asian (SAS)

AF:

0.00

AC:

AN:

71894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5318

European-Non Finnish (NFE)

AF:

9.98e-7

AC:

AN:

1001528

Other (OTH)

AF:

0.00

AC:

AN:

53756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

4.2

H;.

PhyloP100

9.5

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.81

Loss of sheet (P = 0.0817);.;

MVP

0.83

MPC

0.17

ClinPred

1.0

GERP RS

5.6

Varity_R

0.93

gMVP

0.72

Mutation Taster

=19/81

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over