X-47198833-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_003334.4(UBA1):c.31C>T(p.Arg11Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000909 in 1,210,359 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 1 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

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 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, UBA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.31139648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.31C>T	p.Arg11Cys	missense_variant	2/26	ENST00000335972.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.31C>T	p.Arg11Cys	missense_variant	2/26	1	NM_003334.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112143 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34289

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183430 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098216 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112143 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34289

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000283

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

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

Invitae

Aug 09, 2022

This variant is present in population databases (no rsID available, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 11 of the UBA1 protein (p.Arg11Cys). This variant has not been reported in the literature in individuals affected with UBA1-related conditions. 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1424507). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T;T;T;T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L;.;.;.;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.6	N;D;D;D;D;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.029	D;D;T;D;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T;T;T;T
Polyphen		0.0090	B;.;.;.;.;B;.
Vest4		0.34
MutPred		0.24		Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);.;.;.;Loss of MoRF binding (P = 9e-04);.;
MVP		0.54
MPC		0.63
ClinPred		0.56	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.82

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: rs1556786387; hg19: chrX-47058232;