5-103552305-A-T

Variant names:

• chr5-103552305-A-T
• NM_031438.4:c.1190T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_031438.4(NUDT12):​c.1190T>A​(p.Met397Lys) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NUDT12 NM_031438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

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]

ENSG00000295164 (HGNC:):

ACMG classification

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, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4	c.1190T>A	p.Met397Lys	missense_variant	Exon 6 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.1136T>A	p.Met379Lys	missense_variant	Exon 6 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.1190T>A	p.Met397Lys	missense_variant	Exon 6 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.1136T>A	p.Met379Lys	missense_variant	Exon 6 of 7		XP_005272154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT12	ENST00000230792.7	c.1190T>A	p.Met397Lys	missense_variant	Exon 6 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.1136T>A	p.Met379Lys	missense_variant	Exon 6 of 7	2		ENSP00000424521.1
ENSG00000295164	ENST00000728393.1	n.93-94A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1190T>A (p.M397K) alteration is located in exon 6 (coding exon 5) of the NUDT12 gene. This alteration results from a T to A substitution at nucleotide position 1190, causing the methionine (M) at amino acid position 397 to be replaced by a lysine (K). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.87		Gain of ubiquitination at M397 (P = 0.0325);.;
MVP		0.92
MPC		0.20
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.92
Mutation Taster		=13/87	disease causing

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

hg19: chr5-102888006;