rs1409013948

Positions:

• chrX-47201533-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003334.4(UBA1):​c.734G>A​(p.Gly245Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,226 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93

Genes affected

UBA1 (HGNC:12469): (ubiquitin like modifier activating enzyme 1) The protein encoded by this gene catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation. This gene complements an X-linked mouse temperature-sensitive defect in DNA synthesis, and thus may function in DNA repair. It is part of a gene cluster on chromosome Xp11.23. Alternatively spliced transcript variants that encode the same protein have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UBA1. . Gene score misZ 3.4752 (greater than the threshold 3.09). GenCC has associacion of gene with infantile-onset X-linked spinal muscular atrophy, inflammatory disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBA1	NM_003334.4	c.734G>A	p.Gly245Glu	missense_variant	8/26	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.734G>A	p.Gly245Glu	missense_variant	8/26	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8	c.734G>A	p.Gly245Glu	missense_variant	8/26	1		ENSP00000366568.4
UBA1	ENST00000442035.5	c.776G>A	p.Gly259Glu	missense_variant	9/9	5		ENSP00000389583.1
UBA1	ENST00000412206.5	c.734G>A	p.Gly245Glu	missense_variant	8/8	5		ENSP00000415033.1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112226 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34374

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112226 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2017

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with UBA1-related disease. This sequence change replaces glycine with glutamic acid at codon 245 of the UBA1 protein (p.Gly245Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;.
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.2	M;.;.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.99	D;.;.;D
Vest4		0.83
MutPred		0.44		Gain of disorder (P = 0.0832);Gain of disorder (P = 0.0832);.;Gain of disorder (P = 0.0832);
MVP		0.82
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.89
gMVP		0.97

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: rs1409013948; hg19: chrX-47060932;