5-103558928-A-T

Variant names:

• chr5-103558928-A-T
• NM_031438.4:c.747T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031438.4(NUDT12):​c.747T>A​(p.Phe249Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUDT12 NM_031438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4	c.747T>A	p.Phe249Leu	missense_variant	Exon 3 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.693T>A	p.Phe231Leu	missense_variant	Exon 3 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.747T>A	p.Phe249Leu	missense_variant	Exon 3 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.693T>A	p.Phe231Leu	missense_variant	Exon 3 of 7		XP_005272154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT12	ENST00000230792.7	c.747T>A	p.Phe249Leu	missense_variant	Exon 3 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.693T>A	p.Phe231Leu	missense_variant	Exon 3 of 7	2		ENSP00000424521.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.747T>A (p.F249L) alteration is located in exon 3 (coding exon 2) of the NUDT12 gene. This alteration results from a T to A substitution at nucleotide position 747, causing the phenylalanine (F) at amino acid position 249 to be replaced by a leucine (L). 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	0.94
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	0.062
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		1.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.20
Sift	Benign	0.044	D;D
Sift4G	Benign	0.54	T;T
Polyphen		0.033	B;D
Vest4		0.76
MutPred		0.62		Gain of loop (P = 0.0045);.;
MVP		0.54
MPC		0.18
ClinPred		0.86	D
GERP RS		2.6
Varity_R		0.40
gMVP		0.74
Mutation Taster		=19/81	disease causing

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

hg19: chr5-102894629;