5-103556072-G-A

Variant names:

• chr5-103556072-G-A
• rs144015299
• NM_031438.4:c.823C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031438.4(NUDT12):​c.823C>T​(p.Leu275Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,609,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NUDT12 NM_031438.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.112107575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4	c.823C>T	p.Leu275Phe	missense_variant	Exon 4 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.769C>T	p.Leu257Phe	missense_variant	Exon 4 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.823C>T	p.Leu275Phe	missense_variant	Exon 4 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.769C>T	p.Leu257Phe	missense_variant	Exon 4 of 7		XP_005272154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT12	ENST00000230792.7	c.823C>T	p.Leu275Phe	missense_variant	Exon 4 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.769C>T	p.Leu257Phe	missense_variant	Exon 4 of 7	2		ENSP00000424521.1
NUDT12	ENST00000515407.1	n.18C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 151848 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000202 AC: 50 AN: 247856 AF XY: 0.000216

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00233

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000193 AC: 281 AN: 1457218 Hom.: 0 Cov.: 32 AF XY: 0.000212 AC XY: 154 AN XY: 724810

African (AFR) AF: 0.0000601 AC: 2 AN: 33266

American (AMR) AF: 0.000113 AC: 5 AN: 44254

Ashkenazi Jewish (ASJ) AF: 0.00201 AC: 52 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00522 AC: 30 AN: 5750

European-Non Finnish (NFE) AF: 0.000153 AC: 170 AN: 1109716

Other (OTH) AF: 0.000333 AC: 20 AN: 60148

GnomAD4 genome AF: 0.000217 AC: 33 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74298

African (AFR) AF: 0.0000482 AC: 2 AN: 41478

American (AMR) AF: 0.000262 AC: 4 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67914

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.823C>T (p.L275F) alteration is located in exon 4 (coding exon 3) of the NUDT12 gene. This alteration results from a C to T substitution at nucleotide position 823, causing the leucine (L) at amino acid position 275 to be replaced by a phenylalanine (F). 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	0.33
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.034
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		3.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.13
Sift	Benign	0.11	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.014	B;B
Vest4		0.73
MVP		0.65
MPC		0.038
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.22
gMVP		0.70
Mutation Taster		=38/62	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: rs144015299; hg19: chr5-102891773;