X-47198894-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003334.4(UBA1):c.92C>G(p.Ser31Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,238 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S31S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.28299385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.92C>G	p.Ser31Cys	missense_variant	2/26	ENST00000335972.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.92C>G	p.Ser31Cys	missense_variant	2/26	1	NM_003334.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183506 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098238 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363592

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Dec 31, 2021

This variant is present in population databases (no rsID available, gnomAD 0.001%). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with UBA1-related conditions. This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 31 of the UBA1 protein (p.Ser31Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.069	T;.;T;T;T;T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T;T;T;T;.;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.7	L;.;.;.;.;L;.
MutationTaster	Benign	0.54	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.77	N;N;N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.052	T;D;D;D;D;T;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D
Polyphen		0.61	P;.;.;.;.;P;.
Vest4		0.17
MutPred		0.30		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;.;.;Gain of sheet (P = 0.0266);.;
MVP		0.67
MPC		0.53
ClinPred		0.31	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.85

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: rs1556786446; hg19: chrX-47058293;