rs7298565

Variant names:

• chr12-109499729-G-A
• rs7298565
• NM_130466.4:c.1037G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-109499729-G-A
• chr12-109499729-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130466.4(UBE3B):​c.1037G>A​(p.Arg346Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,611,796 control chromosomes in the GnomAD database, including 224,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R346W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.57 (25833 hom., cov: 32)
  • Exomes 𝑓: 0.52 (198682 hom.)
• Consequence: UBE3B NM_130466.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.26
• Publications: 72 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9271438E-6).
• BP6: Variant 12-109499729-G-A is Benign according to our data. Variant chr12-109499729-G-A is described in ClinVar as Benign. ClinVar VariationId is 1600613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

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.1037G>A	p.Arg346Gln	missense	Exon 12 of 28	NP_569733.2
	UBE3B	NM_183415.3		c.1037G>A	p.Arg346Gln	missense	Exon 12 of 28	NP_904324.1	Q7Z3V4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3B	ENST00000342494.8	TSL:1 MANE Select	c.1037G>A	p.Arg346Gln	missense	Exon 12 of 28	ENSP00000340596.3	Q7Z3V4-1
	UBE3B	ENST00000434735.6	TSL:1	c.1037G>A	p.Arg346Gln	missense	Exon 12 of 28	ENSP00000391529.2	Q7Z3V4-1
	UBE3B	ENST00000539599.5	TSL:1	c.1037G>A	p.Arg346Gln	missense	Exon 11 of 23	ENSP00000443131.1	F5H5T5

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86593 AN: 151902 Hom.: 25784 Cov.: 32

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.583

GnomAD2 exomes AF: 0.501 AC: 125037 AN: 249666 AF XY: 0.497

Gnomad AFR exome AF: 0.745

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.467

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.517 AC: 755039 AN: 1459774 Hom.: 198682 Cov.: 48 AF XY: 0.515 AC XY: 374028 AN XY: 726222

African (AFR) AF: 0.740 AC: 24653 AN: 33308

American (AMR) AF: 0.467 AC: 20796 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14318 AN: 26066

East Asian (EAS) AF: 0.297 AC: 11746 AN: 39532

South Asian (SAS) AF: 0.418 AC: 35933 AN: 86052

European-Finnish (FIN) AF: 0.469 AC: 25036 AN: 53350

Middle Eastern (MID) AF: 0.583 AC: 3357 AN: 5754

European-Non Finnish (NFE) AF: 0.529 AC: 587911 AN: 1110866

Other (OTH) AF: 0.519 AC: 31289 AN: 60308

GnomAD4 genome AF: 0.570 AC: 86706 AN: 152022 Hom.: 25833 Cov.: 32 AF XY: 0.561 AC XY: 41664 AN XY: 74316

African (AFR) AF: 0.735 AC: 30517 AN: 41494

American (AMR) AF: 0.503 AC: 7676 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1849 AN: 3472

East Asian (EAS) AF: 0.296 AC: 1528 AN: 5162

South Asian (SAS) AF: 0.389 AC: 1872 AN: 4818

European-Finnish (FIN) AF: 0.464 AC: 4903 AN: 10558

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36429 AN: 67936

Other (OTH) AF: 0.583 AC: 1234 AN: 2116

Alfa AF: 0.547 Hom.: 90005

Bravo AF: 0.584

TwinsUK AF: 0.525 AC: 1947

ALSPAC AF: 0.510 AC: 1964

ESP6500AA AF: 0.731 AC: 3222

ESP6500EA AF: 0.532 AC: 4578

ExAC AF: 0.510 AC: 61878

Asia WGS AF: 0.388 AC: 1349 AN: 3478

EpiCase AF: 0.555

EpiControl AF: 0.548

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Oculocerebrofacial syndrome, Kaufman type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.36
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.5	N
PhyloP100		7.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.32
ClinPred		0.041	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.087
Mutation Taster		=99/1	polymorphism (auto)

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: rs7298565; hg19: chr12-109937534; COSMIC: COSV55098192; COSMIC: COSV55098192;