chr12-109483552-A-G

Variant names:

• chr12-109483552-A-G
• rs672601304
• NM_130466.4:c.1A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_130466.4(UBE3B):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,342 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 no classification for the single variant (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: UBE3B NM_130466.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.93
• Publications: 2 publications found

Genes affected

UBE3B (HGNC:13478): (ubiquitin protein ligase E3B) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin-protein ligases. This gene encodes a member of the E3 ubiquitin-conjugating enzyme family which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme and transfers the ubiquitin to the targeted substrates. A HECT (homology to E6-AP C-terminus) domain in the C-terminus of the longer isoform of this protein is the catalytic site of ubiquitin transfer and forms a complex with E2 conjugases. Shorter isoforms of this protein which lack the C-terminal HECT domain are therefore unlikely to bind E2 enzymes. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2012]

UBE3B Gene-Disease associations (from GenCC):

• oculocerebrofacial syndrome, Kaufman type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 107 codons. Genomic position: 109486048. Lost 0.099 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130466.4. 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
	UBE3B	NM_130466.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 3 of 28	NP_569733.2
	UBE3B	NM_183415.3		c.1A>G	p.Met1?	start_lost	Exon 3 of 28	NP_904324.1	Q7Z3V4-1
	UBE3B	NM_001270449.2		c.1A>G	p.Met1?	start_lost	Exon 3 of 9	NP_001257378.1	Q7Z3V4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3B	ENST00000342494.8	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 3 of 28	ENSP00000340596.3	Q7Z3V4-1
	UBE3B	ENST00000434735.6	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 3 of 28	ENSP00000391529.2	Q7Z3V4-1
	UBE3B	ENST00000539599.5	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 2 of 23	ENSP00000443131.1	F5H5T5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410342 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698358

African (AFR) AF: 0.00 AC: 0 AN: 31160

American (AMR) AF: 0.00 AC: 0 AN: 32834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39208

South Asian (SAS) AF: 0.00 AC: 0 AN: 77886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090662

Other (OTH) AF: 0.0000172 AC: 1 AN: 58062

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000497 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.29	T
PhyloP100		7.9
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.99		Loss of disorder (P = 0.0986)
MVP		0.81
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.64
Mutation Taster		=1/199	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: rs672601304; hg19: chr12-109921357;