19-34438657-T-C

Position:

• chr19-34438657-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_005499.3(UBA2):​c.472T>C​(p.Cys158Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBA2 NM_005499.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBA2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA2	NM_005499.3	c.472T>C	p.Cys158Arg	missense_variant	6/17	ENST00000246548.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA2	ENST00000246548.9	c.472T>C	p.Cys158Arg	missense_variant	6/17	1	NM_005499.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ACCES syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ACCES syndrome (MIM#619959). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been described (PMID: 34040189). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated binding site within the ThiF family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	4.4	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D;.;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.82		Gain of disorder (P = 0.0133);.;.;
MVP		0.91
MPC		3.2
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-34929562;