X-47198908-G-A

Variant summary

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

The NM_003334.4(UBA1):c.106G>A(p.Val36Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,105 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. V36V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

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=0.27140892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.106G>A	p.Val36Met	missense_variant	2/26	ENST00000335972.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.106G>A	p.Val36Met	missense_variant	2/26	1	NM_003334.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098105 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363461

Gnomad4 AFR exome AF: 0.0000379

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

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 07, 2018

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with UBA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 36 of the UBA1 protein (p.Val36Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.045	T;.;T;T;T;T;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T;T;T;T;T;.;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.34	N;.;.;.;.;N;.
MutationTaster	Benign	0.89	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.39	N;N;N;N;N;N;N
REVEL	Benign	0.084
Sift	Benign	0.16	T;T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;B;.
Vest4		0.26
MutPred		0.14		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;.;.;Gain of loop (P = 0.1069);.;
MVP		0.75
MPC		0.58
ClinPred		0.83	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.45

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: rs990805894; hg19: chrX-47058307;