Genetic Variant NUDT12:p.Pro323Ala (chr5-103554851-G-C) – 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.967C>G(p.Pro323Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NUDT12
NM_031438.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.54

Publications

1 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, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4 link	c.967C>G	p.Pro323Ala	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000230792.7	NP_113626.1	Q9BQG2-1
NUDT12	NM_001300741.2 link	c.913C>G	p.Pro305Ala	missense_variant, splice_region_variant	Exon 5 of 7		NP_001287670.1	Q9BQG2-2
NUDT12	XM_005272095.2 link	c.967C>G	p.Pro323Ala	missense_variant, splice_region_variant	Exon 5 of 7		XP_005272152.1	Q9BQG2-1
NUDT12	XM_005272097.4 link	c.913C>G	p.Pro305Ala	missense_variant, splice_region_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.967C>G	p.Pro323Ala	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_031438.4	ENSP00000230792.2	Q9BQG2-1
NUDT12	ENST00000507423.1 link	c.913C>G	p.Pro305Ala	missense_variant, splice_region_variant	Exon 5 of 7	2		ENSP00000424521.1	Q9BQG2-2
NUDT12	ENST00000515407.1 link	n.162C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1284004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

643544

African (AFR)

AF:

0.00

AC:

AN:

27280

American (AMR)

AF:

0.00

AC:

AN:

34102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22970

East Asian (EAS)

AF:

0.00

AC:

AN:

35932

South Asian (SAS)

AF:

0.00

AC:

AN:

71256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

982928

Other (OTH)

AF:

0.00

AC:

AN:

53034

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.967C>G (p.P323A) alteration is located in exon 5 (coding exon 4) of the NUDT12 gene. This alteration results from a C to G substitution at nucleotide position 967, causing the proline (P) at amino acid position 323 to be replaced by an alanine (A). 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

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.032

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

9.5

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.82

Gain of catalytic residue at P323 (P = 0.0736);.;

MVP

0.81

MPC

0.16

ClinPred

1.0

GERP RS

5.6

Varity_R

0.95

gMVP

0.56

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over