chr12-109483575-G-A

Variant names:

• chr12-109483575-G-A
• rs757679020
• NM_130466.4:c.24G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_130466.4(UBE3B):​c.24G>A​(p.Ser8Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,596,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: UBE3B NM_130466.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.185
• Publications: 1 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_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-109483575-G-A is Benign according to our data. Variant chr12-109483575-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2169130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.185 with no splicing effect.

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.24G>A	p.Ser8Ser	synonymous	Exon 3 of 28	NP_569733.2
	UBE3B	NM_183415.3		c.24G>A	p.Ser8Ser	synonymous	Exon 3 of 28	NP_904324.1	Q7Z3V4-1
	UBE3B	NM_001270449.2		c.24G>A	p.Ser8Ser	synonymous	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.24G>A	p.Ser8Ser	synonymous	Exon 3 of 28	ENSP00000340596.3	Q7Z3V4-1
	UBE3B	ENST00000434735.6	TSL:1	c.24G>A	p.Ser8Ser	synonymous	Exon 3 of 28	ENSP00000391529.2	Q7Z3V4-1
	UBE3B	ENST00000539599.5	TSL:1	c.24G>A	p.Ser8Ser	synonymous	Exon 2 of 23	ENSP00000443131.1	F5H5T5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000300 AC: 7 AN: 233458 AF XY: 0.0000474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000925

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000145 AC: 21 AN: 1443966 Hom.: 0 Cov.: 31 AF XY: 0.0000195 AC XY: 14 AN XY: 718216

African (AFR) AF: 0.0000309 AC: 1 AN: 32368

American (AMR) AF: 0.000127 AC: 5 AN: 39252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83100

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53164

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5660

European-Non Finnish (NFE) AF: 0.00000994 AC: 11 AN: 1106254

Other (OTH) AF: 0.0000168 AC: 1 AN: 59596

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000714 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.6
DANN	Benign	0.83
PhyloP100		0.18

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: rs757679020; hg19: chr12-109921380; COSMIC: COSV55091100;