4-102809837-G-A

Position:

• chr4-102809837-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001300795.2(UBE2D3):​c.-45C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,512 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: 6.8e-7 (0 hom.)
• Consequence: UBE2D3 NM_001300795.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37

Genes affected

UBE2D3 (HGNC:12476): (ubiquitin conjugating enzyme E2 D3) 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: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme functions in the ubiquitination of the tumor-suppressor protein p53, which is induced by an E3 ubiquitin-protein ligase. [provided by RefSeq, Jan 2017]

UBE2D3 (HGNC:):

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/exons	MANE	Protein	UniProt
UBE2D3	NM_181891.3	c.43C>T	p.Arg15Cys	missense_variant	3/8	ENST00000453744.7	NP_871620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE2D3	ENST00000453744.7	c.43C>T	p.Arg15Cys	missense_variant	3/8	1	NM_181891.3	ENSP00000396901.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461512 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727042

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

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 05, 2024

The c.49C>T (p.R17C) alteration is located in exon 2 (coding exon 2) of the UBE2D3 gene. This alteration results from a C to T substitution at nucleotide position 49, causing the arginine (R) at amino acid position 17 to be replaced by a cysteine (C). 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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T;T;T;.;T;T;T;T;.;T;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	.;T;T;.;.;T;.;T;.;.;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.7	M;M;.;M;M;M;M;.;M;M;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.5	D;D;.;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.010	D;D;.;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.032	D;D;D;D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.010	B;B;.;B;B;B;B;.;B;B;B;.;.;.
Vest4		0.54
MutPred		0.38		Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);.;Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);.;Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);.;Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);
MVP		0.82
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.87

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: rs1395430286; hg19: chr4-103730994; COSMIC: COSV57662727;