NM_031438.4:c.967C>A

Variant names:

• chr5-103554851-G-T
• rs537642597
• NM_031438.4:c.967C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031438.4(NUDT12):​c.967C>A​(p.Pro323Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000949 in 105,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P323L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000095 (0 hom., cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NUDT12 NM_031438.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.54
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4	c.967C>A	p.Pro323Thr	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.913C>A	p.Pro305Thr	missense_variant, splice_region_variant	Exon 5 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.967C>A	p.Pro323Thr	missense_variant, splice_region_variant	Exon 5 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.913C>A	p.Pro305Thr	missense_variant, splice_region_variant	Exon 5 of 7		XP_005272154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUDT12	ENST00000230792.7	c.967C>A	p.Pro323Thr	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.913C>A	p.Pro305Thr	missense_variant, splice_region_variant	Exon 5 of 7	2		ENSP00000424521.1
NUDT12	ENST00000515407.1	n.162C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.00000950 AC: 1 AN: 105240 Hom.: 0 Cov.: 32

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: 0.000347

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000580 AC: 1 AN: 172360 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.79e-7 AC: 1 AN: 1283994 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 643536

African (AFR) AF: 0.00 AC: 0 AN: 27280

American (AMR) AF: 0.00 AC: 0 AN: 34102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22970

East Asian (EAS) AF: 0.00 AC: 0 AN: 35932

South Asian (SAS) AF: 0.00 AC: 0 AN: 71256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5276

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 982918

Other (OTH) AF: 0.00 AC: 0 AN: 53034

GnomAD4 genome AF: 0.00000949 AC: 1 AN: 105362 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 50788

African (AFR) AF: 0.00 AC: 0 AN: 31670

American (AMR) AF: 0.00 AC: 0 AN: 10908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2196

East Asian (EAS) AF: 0.00 AC: 0 AN: 4088

South Asian (SAS) AF: 0.000347 AC: 1 AN: 2882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 186

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45288

Other (OTH) AF: 0.00 AC: 0 AN: 1330

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.6	H;.
PhyloP100		9.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.83		Gain of sheet (P = 0.0827);.;
MVP		0.82
MPC		0.18
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.66
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs537642597; hg19: chr5-102890552;