7-2249989-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_002452.4(NUDT1):c.285C>T(p.Pro95=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,066 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: NUDT1 NM_002452.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.153

Genes affected

NUDT1 (HGNC:8048): (nudix hydrolase 1) Misincorporation of oxidized nucleoside triphosphates into DNA/RNA during replication and transcription can cause mutations that may result in carcinogenesis or neurodegeneration. The protein encoded by this gene is an enzyme that hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP, to monophosphates, thereby preventing misincorporation. The encoded protein is localized mainly in the cytoplasm, with some in the mitochondria, suggesting that it is involved in the sanitization of nucleotide pools both for nuclear and mitochondrial genomes. Several alternatively spliced transcript variants, some of which encode distinct isoforms, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A rare single-nucleotide polymorphism that results in the production of an additional, longer isoform (p26) has been described. [provided by RefSeq, Dec 2018]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-2249989-C-T is Benign according to our data. Variant chr7-2249989-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2657227.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.153 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00134 (1962/1461724) while in subpopulation MID AF= 0.0182 (105/5768). AF 95% confidence interval is 0.0154. There are 7 homozygotes in gnomad4_exome. There are 1073 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUDT1	NM_002452.4	c.285C>T	p.Pro95=	synonymous_variant	3/4	ENST00000356714.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUDT1	ENST00000356714.6	c.285C>T	p.Pro95=	synonymous_variant	3/4	1	NM_002452.4	P1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 223 AN: 152224 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00185 AC: 464 AN: 251090 Hom.: 3 AF XY: 0.00201 AC XY: 273 AN XY: 135764

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00725

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00134 AC: 1962 AN: 1461724 Hom.: 7 Cov.: 31 AF XY: 0.00148 AC XY: 1073 AN XY: 727172

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00685

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00410

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152342 Hom.: 2 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74490

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00175

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

NUDT1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	5.7
Dann	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs143614396; hg19: chr7-2289624;