X-47206074-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003334.4(UBA1):c.1702C>G(p.Leu568Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,203,705 control chromosomes in the GnomAD database, including 55 homozygotes. There are 1,397 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., 172 hem., cov: 24)

Exomes 𝑓: 0.0035 ( 51 hom. 1225 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.09

Variant links:

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 links:

LOC105373194 (HGNC:):

LOC105373194 links:

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]

INE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008150339).

BP6

Variant X-47206074-C-G is Benign according to our data. Variant chrX-47206074-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 368339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47206074-C-G is described in Lovd as [Likely_benign]. Variant chrX-47206074-C-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4 link	c.1702C>G	p.Leu568Val	missense_variant	Exon 15 of 26	ENST00000335972.11	NP_003325.2	P22314-1A0A024R1A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBA1	ENST00000335972.11 link	c.1702C>G	p.Leu568Val	missense_variant	Exon 15 of 26	1	NM_003334.4	ENSP00000338413.6	P22314-1
UBA1	ENST00000377351.8 link	c.1702C>G	p.Leu568Val	missense_variant	Exon 15 of 26	1		ENSP00000366568.4	P22314-1
UBA1	ENST00000490869.1 link	n.465-4C>G		splice_region_variant, intron_variant	Intron 4 of 5	2
INE1	ENST00000456273.1 link	n.*209C>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

458

AN:

111825

Hom.:

Cov.:

AF XY:

0.00509

AC XY:

173

AN XY:

34011

show subpopulations

Gnomad AFR

AF:

0.000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

Gnomad ASJ

AF:

0.0106

Gnomad EAS

AF:

0.0556

Gnomad SAS

AF:

0.00417

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00403

GnomAD3 exomes

AF:

0.00782

AC:

1306

AN:

167034

Hom.:

AF XY:

0.00702

AC XY:

379

AN XY:

54020

show subpopulations

Gnomad AFR exome

AF:

0.000167

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00700

Gnomad EAS exome

AF:

0.0548

Gnomad SAS exome

AF:

0.00337

Gnomad FIN exome

AF:

0.0240

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.00878

GnomAD4 exome

AF:

0.00345

AC:

3772

AN:

1091826

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

1225

AN XY:

358234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000761

Gnomad4 AMR exome

AF:

0.0000290

Gnomad4 ASJ exome

AF:

0.00684

Gnomad4 EAS exome

AF:

0.0632

Gnomad4 SAS exome

AF:

0.00318

Gnomad4 FIN exome

AF:

0.0239

Gnomad4 NFE exome

AF:

0.000484

Gnomad4 OTH exome

AF:

0.00467

GnomAD4 genome

AF:

0.00408

AC:

456

AN:

111879

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

172

AN XY:

34075

show subpopulations

Gnomad4 AFR

AF:

0.000325

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.0106

Gnomad4 EAS

AF:

0.0553

Gnomad4 SAS

AF:

0.00418

Gnomad4 FIN

AF:

0.0253

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00398

Alfa

AF:

0.00324

Hom.:

Bravo

AF:

0.00297

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00193

AC:

ExAC

AF:

0.00755

AC:

914

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 10, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Infantile-onset X-linked spinal muscular atrophy

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

UBA1-related disorder

Benign:1

Mar 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Infantile-onset X-linked spinal muscular atrophy;C5435753:VEXAS syndrome

Benign:1

Mar 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;.

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.040

D;D

Polyphen

1.0

D;D

Vest4

0.23

MVP

0.61

MPC

2.2

ClinPred

0.031

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over