19-34430604-A-C

Position:

• chr19-34430604-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM2 PP2 PP3_Strong PP5_Moderate

The NM_005499.3(UBA2):​c.167A>C​(p.Asn56Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBA2 NM_005499.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.74

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 Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_005499.3 (UBA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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, 0.988
• PP5: Variant 19-34430604-A-C is Pathogenic according to our data. Variant chr19-34430604-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 979177.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA2	NM_005499.3	c.167A>C	p.Asn56Thr	missense_variant	2/17	ENST00000246548.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA2	ENST00000246548.9	c.167A>C	p.Asn56Thr	missense_variant	2/17	1	NM_005499.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2020

De novo variant with confirmed parentage in a patient with developmental delay and multiple congenital anomalies previously tested at GeneDx 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 N56T as a likely pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	5.1	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.97		Loss of MoRF binding (P = 0.1889);
MVP		0.81
MPC		2.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075242496; hg19: chr19-34921509;