NM_080911.3:c.262C>T

Variant names:

• chr12-109098561-C-T
• rs151095402
• NM_080911.3:c.262C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_080911.3(UNG):​c.262C>T​(p.Arg88Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00126 in 1,613,316 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: UNG NM_080911.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1 O:1
• Conservation: PhyloP100: 4.97
• Publications: 14 publications found

Genes affected

UNG (HGNC:12572): (uracil DNA glycosylase) This gene encodes one of several uracil-DNA glycosylases. One important function of uracil-DNA glycosylases is to prevent mutagenesis by eliminating uracil from DNA molecules by cleaving the N-glycosylic bond and initiating the base-excision repair (BER) pathway. Uracil bases occur from cytosine deamination or misincorporation of dUMP residues. Alternative promoter usage and splicing of this gene leads to two different isoforms: the mitochondrial UNG1 and the nuclear UNG2. The UNG2 term was used as a previous symbol for the CCNO gene (GeneID 10309), which has been confused with this gene, in the literature and some databases. [provided by RefSeq, Nov 2010]

ALKBH2 (HGNC:32487): (alkB homolog 2, alpha-ketoglutarate dependent dioxygenase) The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the specific DNA lesions generated in single-stranded DNA. ALKBH2 and ALKBH3 (MIM 610603) are E. coli AlkB homologs that catalyze the removal of 1-methyladenine and 3-methylcytosine (Duncan et al., 2002 [PubMed 12486230]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.082110554).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000978 (149/152352) while in subpopulation AMR AF = 0.00176 (27/15308). AF 95% confidence interval is 0.00124. There are 1 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080911.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNG	NM_080911.3	MANE Select	c.262C>T	p.Arg88Cys	missense	Exon 2 of 7	NP_550433.1	E5KTA5
	UNG	NM_003362.4		c.235C>T	p.Arg79Cys	missense	Exon 1 of 6	NP_003353.1	P13051-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNG	ENST00000242576.7	TSL:1 MANE Select	c.262C>T	p.Arg88Cys	missense	Exon 2 of 7	ENSP00000242576.3	P13051-1
	UNG	ENST00000336865.6	TSL:1	c.235C>T	p.Arg79Cys	missense	Exon 1 of 6	ENSP00000337398.2	P13051-2
	UNG	ENST00000446767.2	TSL:1	n.235C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000400287.2	Q68DM5

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00119 AC: 292 AN: 244470 AF XY: 0.00128

Gnomad AFR exome AF: 0.000327

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00129 AC: 1887 AN: 1460964 Hom.: 4 Cov.: 33 AF XY: 0.00137 AC XY: 992 AN XY: 726722

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86248

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52576

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5766

European-Non Finnish (NFE) AF: 0.00139 AC: 1543 AN: 1111958

Other (OTH) AF: 0.00139 AC: 84 AN: 60382

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74500

African (AFR) AF: 0.000385 AC: 16 AN: 41580

American (AMR) AF: 0.00176 AC: 27 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00161 Hom.: 2

Bravo AF: 0.00115

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00113 AC: 137

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	Hyper-IgM syndrome type 5 (6)
-	5	-	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.082	T
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.69
MVP		0.90
MPC		0.54
ClinPred		0.065	T
GERP RS		4.2
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.62
gMVP		0.52
Mutation Taster		=55/45	polymorphism

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: rs151095402; hg19: chr12-109536366;