5-103552368-C-A

Variant names:

• chr5-103552368-C-A
• rs1748681369
• NM_031438.4:c.1127G>T

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.1127G>T​(p.Gly376Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: NUDT12 NM_031438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4	c.1127G>T	p.Gly376Val	missense_variant	Exon 6 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.1073G>T	p.Gly358Val	missense_variant	Exon 6 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.1127G>T	p.Gly376Val	missense_variant	Exon 6 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.1073G>T	p.Gly358Val	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.1127G>T	p.Gly376Val	missense_variant	Exon 6 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.1073G>T	p.Gly358Val	missense_variant	Exon 6 of 7	2		ENSP00000424521.1
ENSG00000295164	ENST00000728393.1	n.93-31C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727124

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

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111904

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1127G>T (p.G376V) alteration is located in exon 6 (coding exon 5) of the NUDT12 gene. This alteration results from a G to T substitution at nucleotide position 1127, causing the glycine (G) at amino acid position 376 to be replaced by a valine (V). 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	0.81
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.6	H;.
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.92		Gain of sheet (P = 0.0149);.;
MVP		0.96
MPC		0.19
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.87
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs1748681369; hg19: chr5-102888069;