3-69055893-T-C

Variant names:

• chr3-69055893-T-C
• rs1394223577
• NM_003968.4:c.1261A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_003968.4(UBA3):​c.1261A>G​(p.Ile421Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,652 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UBA3 NM_003968.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

Genes affected

UBA3 (HGNC:12470): (ubiquitin like modifier activating enzyme 3) 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 E1 ubiquitin-activating enzyme family. The encoded enzyme associates with AppBp1, an amyloid beta precursor protein binding protein, to form a heterodimer, and then the enzyme complex activates NEDD8, a ubiquitin-like protein, which regulates cell division, signaling and embryogenesis. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EOGT-DT (HGNC:55605): (EOGT divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a mutagenesis_site Impairs NEDD8 transfer to UBE2M. (size 0) in uniprot entity UBA3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34468952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA3	NM_003968.4	c.1261A>G	p.Ile421Val	missense_variant	Exon 17 of 18	ENST00000361055.9	NP_003959.3
UBA3	NM_198195.2	c.1219A>G	p.Ile407Val	missense_variant	Exon 16 of 17		NP_937838.1
UBA3	NM_001363861.1	c.1138A>G	p.Ile380Val	missense_variant	Exon 15 of 16		NP_001350790.1
UBA3	XM_011534210.2	c.1180A>G	p.Ile394Val	missense_variant	Exon 16 of 17		XP_011532512.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA3	ENST00000361055.9	c.1261A>G	p.Ile421Val	missense_variant	Exon 17 of 18	1	NM_003968.4	ENSP00000354340.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460652 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726656

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1261A>G (p.I421V) alteration is located in exon 17 (coding exon 17) of the UBA3 gene. This alteration results from a A to G substitution at nucleotide position 1261, causing the isoleucine (I) at amino acid position 421 to be replaced by a valine (V). 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	0.18
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.93	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.022	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.45, 0.19	.;B;B
Vest4		0.48
MutPred		0.64		.;Gain of disorder (P = 0.0909);.;
MVP		0.35
MPC		0.43
ClinPred		0.70	D
GERP RS		5.8
Varity_R		0.52
gMVP		0.15

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: rs1394223577; hg19: chr3-69105044;