rs1555729503

Variant names:

• chr19-34450307-CTA-C
• rs1555729503
• NM_005499.3:c.816_817delAT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005499.3(UBA2):​c.816_817delAT​(p.Trp273AlafsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBA2 NM_005499.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.37
• Publications: 1 publications found

Genes affected

UBA2 (HGNC:30661): (ubiquitin like modifier activating enzyme 2) Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1; MIM 601912), or sumoylation, regulates protein structure and intracellular localization. SAE1 (MIM 613294) and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins (Okuma et al., 1999 [PubMed 9920803]).[supplied by OMIM, Mar 2010]

UBA2 Gene-Disease associations (from GenCC):

• ACCES syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-34450307-CTA-C is Pathogenic according to our data. Variant chr19-34450307-CTA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 521193.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005499.3. 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
	UBA2	NM_005499.3	MANE Select	c.816_817delAT	p.Trp273AlafsTer13	frameshift	Exon 9 of 17	NP_005490.1	Q9UBT2-1
	UBA2	NM_001411139.1		c.528_529delAT	p.Trp177AlafsTer13	frameshift	Exon 10 of 18	NP_001398068.1	Q9UBT2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA2	ENST00000246548.9	TSL:1 MANE Select	c.816_817delAT	p.Trp273AlafsTer13	frameshift	Exon 9 of 17	ENSP00000246548.3	Q9UBT2-1
	UBA2	ENST00000439527.6	TSL:2	c.528_529delAT	p.Trp177AlafsTer13	frameshift	Exon 9 of 17	ENSP00000437484.1	Q9UBT2-2
	UBA2	ENST00000590048.6	TSL:3	c.732_733delAT	p.Trp245AlafsTer13	frameshift	Exon 8 of 8	ENSP00000467433.2	K7EPL2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	ACCES syndrome (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

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

Other links and lift over

dbSNP: rs1555729503; hg19: chr19-34941212;