12-109483591-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3B	NM_130466.4	c.40G>T	p.Asp14Tyr	missense_variant	Exon 3 of 28	ENST00000342494.8	NP_569733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3B	ENST00000342494.8	c.40G>T	p.Asp14Tyr	missense_variant	Exon 3 of 28	1	NM_130466.4	ENSP00000340596.3
UBE3B	ENST00000449510.6	n.40G>T		non_coding_transcript_exon_variant	Exon 3 of 29	5		ENSP00000395802.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T;T;.;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;.;D;D;.;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M;M;.;M;M;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N;D;N;N;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.83
MutPred		0.36		Loss of disorder (P = 0.0151);Loss of disorder (P = 0.0151);Loss of disorder (P = 0.0151);Loss of disorder (P = 0.0151);Loss of disorder (P = 0.0151);Loss of disorder (P = 0.0151);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs771722819; hg19: chr12-109921396;