chrX-47202740-G-A

Position:

• chrX-47202740-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003334.4(UBA1):​c.1159G>A​(p.Ala387Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,672 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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: 1.92

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]

UBA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UBA1. . Gene score misZ 3.4752 (greater than the threshold 3.09). GenCC has associacion of gene with infantile-onset X-linked spinal muscular atrophy, inflammatory disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBA1	NM_003334.4	c.1159G>A	p.Ala387Thr	missense_variant	11/26	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.1159G>A	p.Ala387Thr	missense_variant	11/26	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8	c.1159G>A	p.Ala387Thr	missense_variant	11/26	1		ENSP00000366568.4
UBA1	ENST00000490869.1	n.48G>A		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096672 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 362132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 12, 2017

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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on UBA1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with a UBA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 387 of the UBA1 protein (p.Ala387Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.97	D;D
Vest4		0.63
MutPred		0.51		Loss of stability (P = 0.0436);Loss of stability (P = 0.0436);
MVP		0.67
MPC		0.59
ClinPred		0.98	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.70
gMVP		0.51

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: rs1556788813; hg19: chrX-47062139;