rs80356545

chrX-47205989-G-AchrX-47205989-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 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 same amino acid change has been previously reported as Uncertain significancein 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

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.1617G>A	p.Met539Ile	missense_variant	15/26	ENST00000335972.11
LOC105373194	XR_949047.4	n.278-639C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.1617G>A	p.Met539Ile	missense_variant	15/26	1	NM_003334.4	P1
UBA1	ENST00000377351.8	c.1617G>A	p.Met539Ile	missense_variant	15/26	1		P1
UBA1	ENST00000490869.1	n.465-89G>A		intron_variant, non_coding_transcript_variant		2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 26, 2021

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on UBA1 function (PMID: 29034082). 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. 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. This variant is not present in population databases (gnomAD no frequency). 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). -

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-47065388;