6-83044438-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198920.3(UBE3D):c.587A>G(p.His196Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: UBE3D NM_198920.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.288

Genes affected

UBE3D (HGNC:21381): (ubiquitin protein ligase E3D) Enables cyclin binding activity; ubiquitin protein ligase activity; and ubiquitin-like protein conjugating enzyme binding activity. Involved in protein autoubiquitination; protein monoubiquitination; and protein polyubiquitination. Part of ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051124692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3D	NM_198920.3	c.587A>G	p.His196Arg	missense_variant	4/10	ENST00000369747.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3D	ENST00000369747.8	c.587A>G	p.His196Arg	missense_variant	4/10	1	NM_198920.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.587A>G (p.H196R) alteration is located in exon 4 (coding exon 4) of the UBE3D gene. This alteration results from a A to G substitution at nucleotide position 587, causing the histidine (H) at amino acid position 196 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	6.6
Dann	Benign	0.17
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.031
Sift	Benign	0.83	T
Sift4G	Benign	0.70	T
Polyphen		0.0060	B
Vest4		0.080
MutPred		0.44		Gain of solvent accessibility (P = 0.039);
MVP		0.030
MPC		0.27
ClinPred		0.041	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1782883427; hg19: chr6-83754157;