Genetic Variant UBA2:p.Gly24Val (chr19-34428503-G-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_005499.3(UBA2):c.71G>T(p.Gly24Val) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UBA2
NM_005499.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.60

Variant links:

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 links:

ENSG00000267024 (HGNC:):

ENSG00000267024 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.6072 (below the threshold of 3.09). Trascript score misZ: 3.5151 (above the threshold of 3.09). GenCC associations: The gene is linked to ACCES syndrome, multiple congenital anomalies/dysmorphic syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 19-34428503-G-T is Pathogenic according to our data. Variant chr19-34428503-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 979175.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA2	NM_005499.3 link	c.71G>T	p.Gly24Val	missense_variant	Exon 1 of 17	ENST00000246548.9	NP_005490.1	Q9UBT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA2	ENST00000246548.9 link	c.71G>T	p.Gly24Val	missense_variant	Exon 1 of 17	1	NM_005499.3	ENSP00000246548.3		Q9UBT2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1150012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

549796

African (AFR)

AF:

0.00

AC:

AN:

24852

American (AMR)

AF:

0.00

AC:

AN:

16246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15028

East Asian (EAS)

AF:

0.00

AC:

AN:

30146

South Asian (SAS)

AF:

0.00

AC:

AN:

25162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4566

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

950464

Other (OTH)

AF:

0.00

AC:

AN:

45868

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ACCES syndrome

Pathogenic:1

Jul 14, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Sep 09, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

De novo variant with confirmed parentage in a patient with cutis aplasia in the published literature (Marble et al., 2017) Not observed in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function We interpret G24V as a likely pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

5.1

H;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-7.3

D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.97

D;.

Vest4

0.89

MutPred

0.89

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);

MVP

0.98

MPC

2.6

ClinPred

1.0

GERP RS

5.1

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.1

Varity_R

0.99

gMVP

0.89

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over