5-103554851-G-A

Variant names:

• chr5-103554851-G-A
• rs537642597
• NM_031438.4:c.967C>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.967C>T​(p.Pro323Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000095 in 105,240 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: 0.0 (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: 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, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUDT12	NM_031438.4	c.967C>T	p.Pro323Ser	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000230792.7	NP_113626.1
NUDT12	NM_001300741.2	c.913C>T	p.Pro305Ser	missense_variant, splice_region_variant	Exon 5 of 7		NP_001287670.1
NUDT12	XM_005272095.2	c.967C>T	p.Pro323Ser	missense_variant, splice_region_variant	Exon 5 of 7		XP_005272152.1
NUDT12	XM_005272097.4	c.913C>T	p.Pro305Ser	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>T	p.Pro323Ser	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_031438.4	ENSP00000230792.2
NUDT12	ENST00000507423.1	c.913C>T	p.Pro305Ser	missense_variant, splice_region_variant	Exon 5 of 7	2		ENSP00000424521.1
NUDT12	ENST00000515407.1	n.162C>T		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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000221

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1284002 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 643542

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

American (AMR) AF: 0.00 AC: 0 AN: 34100

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: 0.00 AC: 0 AN: 982928

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

GnomAD4 genome AF: 0.00000950 AC: 1 AN: 105240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 50680

African (AFR) AF: 0.00 AC: 0 AN: 31566

American (AMR) AF: 0.00 AC: 0 AN: 10882

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4100

South Asian (SAS) AF: 0.00 AC: 0 AN: 2886

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.0000221 AC: 1 AN: 45290

Other (OTH) AF: 0.00 AC: 0 AN: 1306

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.026	T
MutationAssessor	Pathogenic	3.5	M;.
PhyloP100		9.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.82		Gain of sheet (P = 0.1208);.;
MVP		0.81
MPC		0.16
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.67
Mutation Taster		=10/90	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: rs537642597; hg19: chr5-102890552;