rs201031933

chr12-109098564-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_080911.3(UNG):c.265A>G(p.Asn89Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N89S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: UNG NM_080911.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058702707).
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNG	NM_080911.3	c.265A>G	p.Asn89Asp	missense_variant	2/7	ENST00000242576.7
UNG	NM_003362.4	c.238A>G	p.Asn80Asp	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNG	ENST00000242576.7	c.265A>G	p.Asn89Asp	missense_variant	2/7	1	NM_080911.3	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000940 AC: 23 AN: 244626 Hom.: 0 AF XY: 0.0000750 AC XY: 10 AN XY: 133304

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000553

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461000 Hom.: 0 Cov.: 33 AF XY: 0.0000427 AC XY: 31 AN XY: 726742

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74490

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2022

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 89 of the UNG protein (p.Asn89Asp). This variant is present in population databases (rs201031933, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with UNG-related conditions. ClinVar contains an entry for this variant (Variation ID: 532544). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.52	D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.14
Sift	Benign	0.073	T;D
Sift4G	Benign	0.28	T;T
Polyphen		0.51	P;.
Vest4		0.23
MVP		0.72
MPC		0.15
ClinPred		0.032	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.18
gMVP		0.37

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: rs201031933; hg19: chr12-109536369;