19-34428433-A-G

Position:

• chr19-34428433-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005499.3(UBA2):​c.1A>G​(p.Met1?) variant causes a start lost change. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBA2 NM_005499.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.62

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-34428433-A-G is Pathogenic according to our data. Variant chr19-34428433-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985243.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.1A>G	p.Met1?	start_lost	1/17	ENST00000246548.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA2	ENST00000246548.9	c.1A>G	p.Met1?	start_lost	1/17	1	NM_005499.3	P1
UBA2	ENST00000590048.6	c.1A>G	p.Met1?	start_lost	1/8	3
UBA2	ENST00000586313.1	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/12	2
UBA2	ENST00000607361.5	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1114298 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 529718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.18	T;T
Polyphen		0.034	B;.
Vest4		0.42
MutPred		0.90		Loss of MoRF binding (P = 0.1363);Loss of MoRF binding (P = 0.1363);
MVP		0.96
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.92
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs2075210211; hg19: chr19-34919338;