chr12-109483591-G-T

Variant names:

• chr12-109483591-G-T
• rs771722819
• NM_130466.4:c.40G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130466.4(UBE3B):​c.40G>T​(p.Asp14Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,944 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D14N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UBE3B NM_130466.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.82
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Illumina, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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.40G>T	p.Asp14Tyr	missense	Exon 3 of 28	NP_569733.2
	UBE3B	NM_183415.3		c.40G>T	p.Asp14Tyr	missense	Exon 3 of 28	NP_904324.1	Q7Z3V4-1
	UBE3B	NM_001270449.2		c.40G>T	p.Asp14Tyr	missense	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.40G>T	p.Asp14Tyr	missense	Exon 3 of 28	ENSP00000340596.3	Q7Z3V4-1
	UBE3B	ENST00000434735.6	TSL:1	c.40G>T	p.Asp14Tyr	missense	Exon 3 of 28	ENSP00000391529.2	Q7Z3V4-1
	UBE3B	ENST00000539599.5	TSL:1	c.40G>T	p.Asp14Tyr	missense	Exon 2 of 23	ENSP00000443131.1	F5H5T5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456944 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724856

African (AFR) AF: 0.00 AC: 0 AN: 33050

American (AMR) AF: 0.00 AC: 0 AN: 43168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110490

Other (OTH) AF: 0.00 AC: 0 AN: 60156

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.36		Loss of disorder (P = 0.0151)
MVP		0.70
MPC		1.0
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.45
gMVP		0.62
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771722819; hg19: chr12-109921396;