rs1556791125

chrX-47206359-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_003334.4(UBA1):c.1853A>G(p.Tyr618Cys) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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 Likely_pathogenic. Variant got 7 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, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.1853A>G	p.Tyr618Cys	missense_variant	16/26	ENST00000335972.11
LOC105373194	XR_949047.4	n.278-1009T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.1853A>G	p.Tyr618Cys	missense_variant	16/26	1	NM_003334.4	P1
UBA1	ENST00000377351.8	c.1853A>G	p.Tyr618Cys	missense_variant	16/26	1		P1
UBA1	ENST00000490869.1	n.612A>G		non_coding_transcript_exon_variant	6/6	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

Jan 27, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a UBA1-related disease. This sequence change replaces tyrosine with cysteine at codon 618 of the UBA1 protein (p.Tyr618Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-9.0	D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.80		Loss of phosphorylation at Y618 (P = 0.0473);Loss of phosphorylation at Y618 (P = 0.0473);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

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: rs1556791125; hg19: chrX-47065758;