5-103552319-C-T

Variant names:

• chr5-103552319-C-T
• rs372191550
• NM_031438.4:c.1176G>A

Variant summary

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

The NM_031438.4(NUDT12):​c.1176G>A​(p.Met392Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NUDT12 NM_031438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79
• Publications: 1 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: 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.1176G>A	p.Met392Ile	missense_variant	Exon 6 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.1122G>A	p.Met374Ile	missense_variant	Exon 6 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.1176G>A	p.Met392Ile	missense_variant	Exon 6 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.1122G>A	p.Met374Ile	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.1176G>A	p.Met392Ile	missense_variant	Exon 6 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.1122G>A	p.Met374Ile	missense_variant	Exon 6 of 7	2		ENSP00000424521.1
ENSG00000295164	ENST00000728393.1	n.93-80C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251248 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461558 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39684

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111806

Other (OTH) AF: 0.000116 AC: 7 AN: 60386

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1176G>A (p.M392I) alteration is located in exon 6 (coding exon 5) of the NUDT12 gene. This alteration results from a G to A substitution at nucleotide position 1176, causing the methionine (M) at amino acid position 392 to be replaced by an isoleucine (I). 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	0.93
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		5.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.23
Sift	Benign	0.075	T;T
Sift4G	Benign	0.065	T;T
Polyphen		0.89	P;D
Vest4		0.69
MutPred		0.63		Loss of glycosylation at P391 (P = 0.0541);.;
MVP		0.48
MPC		0.18
ClinPred		0.18	T
GERP RS		5.9
Varity_R		0.32
gMVP		0.62
Mutation Taster		=14/86	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

dbSNP: rs372191550; hg19: chr5-102888020;