NM_003968.4:c.1246C>T

Variant names:

• chr3-69056002-G-A
• rs1229077729
• NM_003968.4:c.1246C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003968.4(UBA3):​c.1246C>T​(p.Gln416*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UBA3 NM_003968.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA3	NM_003968.4	MANE Select	c.1246C>T	p.Gln416*	stop_gained splice_region	Exon 16 of 18	NP_003959.3
	UBA3	NM_198195.2		c.1204C>T	p.Gln402*	stop_gained splice_region	Exon 15 of 17	NP_937838.1	Q8TBC4-2
	UBA3	NM_001363861.1		c.1123C>T	p.Gln375*	stop_gained splice_region	Exon 14 of 16	NP_001350790.1	F8W8D4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA3	ENST00000361055.9	TSL:1 MANE Select	c.1246C>T	p.Gln416*	stop_gained splice_region	Exon 16 of 18	ENSP00000354340.4	Q8TBC4-1
	UBA3	ENST00000854662.1		c.1246C>T	p.Gln416*	stop_gained splice_region	Exon 16 of 18	ENSP00000524721.1
	UBA3	ENST00000854663.1		c.1243C>T	p.Gln415*	stop_gained splice_region	Exon 16 of 18	ENSP00000524722.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 243658 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452898 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722652

African (AFR) AF: 0.00 AC: 0 AN: 32722

American (AMR) AF: 0.00 AC: 0 AN: 42654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 84072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109254

Other (OTH) AF: 0.00 AC: 0 AN: 59958

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		10
Vest4		0.82
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.45		Position offset: -2

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

Other links and lift over

dbSNP: rs1229077729; hg19: chr3-69105153;