chrX-47205989-G-A

Variant names:

• chrX-47205989-G-A
• rs80356545
• NM_003334.4:c.1617G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003334.4(UBA1):​c.1617G>A​(p.Met539Ile) 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 Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87
• Publications: 1 publications found

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]

LOC105373194 (HGNC:):

INE1 (HGNC:6060): (inactivation escape 1) X chromosome inactivation provides dosage compensation for the expression level of X-linked genes from the single X in males and the two in females. This X chromosome gene is intronless and was identified because its transcription escapes X inactivation in females. This gene does not make a protein.[provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4	c.1617G>A	p.Met539Ile	missense_variant	Exon 15 of 26	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.1617G>A	p.Met539Ile	missense_variant	Exon 15 of 26	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8	c.1617G>A	p.Met539Ile	missense_variant	Exon 15 of 26	1		ENSP00000366568.4
UBA1	ENST00000490869.1	n.465-89G>A		intron_variant	Intron 4 of 5	2
INE1	ENST00000456273.1	n.*124G>A		downstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

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

Nov 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on UBA1 function (PMID: 29034082). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 539 of the UBA1 protein (p.Met539Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with spinal muscular atrophy (PMID: 18179898, 32181232; Invitae). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.32	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0010	B;B
Vest4		0.77
MutPred		0.86		Gain of catalytic residue at P541 (P = 0.0813);Gain of catalytic residue at P541 (P = 0.0813);
MVP		0.93
MPC		1.3
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.81
gMVP		0.95
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80356545; hg19: chrX-47065388;