5-103552237-G-A

Variant names:

• chr5-103552237-G-A
• rs373323160
• NM_031438.4:c.1258C>T

Variant summary

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

The NM_031438.4(NUDT12):​c.1258C>T​(p.Arg420Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000918 in 1,613,078 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: NUDT12 NM_031438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.56
• 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: 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.1258C>T	p.Arg420Cys	missense_variant	Exon 6 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.1204C>T	p.Arg402Cys	missense_variant	Exon 6 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.1258C>T	p.Arg420Cys	missense_variant	Exon 6 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.1204C>T	p.Arg402Cys	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.1258C>T	p.Arg420Cys	missense_variant	Exon 6 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.1204C>T	p.Arg402Cys	missense_variant	Exon 6 of 7	2		ENSP00000424521.1
ENSG00000295164	ENST00000728393.1	n.93-162G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251070 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.0000931 AC: 136 AN: 1460926 Hom.: 1 Cov.: 31 AF XY: 0.0000991 AC XY: 72 AN XY: 726816

African (AFR) AF: 0.0000598 AC: 2 AN: 33456

American (AMR) AF: 0.0000896 AC: 4 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1111286

Other (OTH) AF: 0.000133 AC: 8 AN: 60350

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1258C>T (p.R420C) alteration is located in exon 6 (coding exon 5) of the NUDT12 gene. This alteration results from a C to T substitution at nucleotide position 1258, causing the arginine (R) at amino acid position 420 to be replaced by a cysteine (C). 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	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		6.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.30
Sift	Benign	0.047	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.97	D;P
Vest4		0.50
MVP		0.65
MPC		0.036
ClinPred		0.45	T
GERP RS		5.8
Varity_R		0.41
gMVP		0.72
Mutation Taster		=39/61	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

dbSNP: rs373323160; hg19: chr5-102887938; COSMIC: COSV50090452; COSMIC: COSV50090452;