NM_080911.3:c.752T>C

Variant names:

• chr12-109103562-T-C
• rs104894380
• NM_080911.3:c.752T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_080911.3(UNG):​c.752T>C​(p.Phe251Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: UNG NM_080911.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.86
• Publications: 6 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]

UNG Gene-Disease associations (from GenCC):

• hyper-IgM syndrome type 5

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 12-109103562-T-C is Pathogenic according to our data. Variant chr12-109103562-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12292.Status of the report is no_assertion_criteria_provided, 0 stars.

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.752T>C	p.Phe251Ser	missense	Exon 6 of 7	NP_550433.1	E5KTA5
	UNG	NM_003362.4		c.725T>C	p.Phe242Ser	missense	Exon 5 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.752T>C	p.Phe251Ser	missense	Exon 6 of 7	ENSP00000242576.3	P13051-1
	UNG	ENST00000336865.6	TSL:1	c.725T>C	p.Phe242Ser	missense	Exon 5 of 6	ENSP00000337398.2	P13051-2
	UNG	ENST00000446767.2	TSL:1	n.*201T>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000400287.2	Q68DM5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyper-IgM syndrome type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.78		Gain of catalytic residue at L252 (P = 0)
MVP		0.87
MPC		0.79
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.94
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs104894380; hg19: chr12-109541367;