Genetic Variant UBA3:p.Met255Ile (chr3-69062108-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003968.4(UBA3):c.765G>A(p.Met255Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UBA3
NM_003968.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.122

Publications

0 publications found

Variant links:

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]

UBA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035767674).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003968.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBA3	NM_003968.4	MANE Select	c.765G>A	p.Met255Ile	missense	Exon 10 of 18	NP_003959.3
UBA3	NM_198195.2		c.723G>A	p.Met241Ile	missense	Exon 9 of 17	NP_937838.1	Q8TBC4-2
UBA3	NM_001363861.1		c.642G>A	p.Met214Ile	missense	Exon 8 of 16	NP_001350790.1	F8W8D4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBA3	ENST00000361055.9	TSL:1 MANE Select	c.765G>A	p.Met255Ile	missense	Exon 10 of 18	ENSP00000354340.4	Q8TBC4-1
UBA3	ENST00000854662.1		c.765G>A	p.Met255Ile	missense	Exon 10 of 18	ENSP00000524721.1
UBA3	ENST00000854663.1		c.765G>A	p.Met255Ile	missense	Exon 10 of 18	ENSP00000524722.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726718

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111372

Other (OTH)

AF:

0.00

AC:

AN:

60336

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.8

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0066

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0028

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

PhyloP100

0.12

PrimateAI

Benign

0.38

PROVEAN

Benign

1.4

REVEL

Benign

0.12

Sift

Benign

0.92

Sift4G

Benign

0.88

Polyphen

0.0

Vest4

0.18

MutPred

0.43

Gain of loop (P = 0.0079)

MVP

0.093

MPC

0.23

ClinPred

0.24

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.70

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over