rs369843264

Positions:

chrX-47202951-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_003334.4(UBA1):c.1242C>T(p.Ser414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,209,369 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 136 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 0.00032 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00034 ( 0 hom. 126 hem. )

Consequence

UBA1
NM_003334.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.49

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant X-47202951-C-T is Benign according to our data. Variant chrX-47202951-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 368334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.49 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4 linkuse as main transcript	c.1242C>T	p.Ser414=	synonymous_variant	12/26	ENST00000335972.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11 linkuse as main transcript	c.1242C>T	p.Ser414=	synonymous_variant	12/26	1	NM_003334.4	P1	P22314-1
UBA1	ENST00000377351.8 linkuse as main transcript	c.1242C>T	p.Ser414=	synonymous_variant	12/26	1		P1	P22314-1
UBA1	ENST00000490869.1 linkuse as main transcript	n.131C>T		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

111686

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

33872

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000285

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000565

Gnomad OTH

AF:

0.000666

GnomAD3 exomes

AF:

0.000300

AC:

AN:

183147

Hom.:

AF XY:

0.000355

AC XY:

AN XY:

67593

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000251

Gnomad NFE exome

AF:

0.000587

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000337

AC:

370

AN:

1097683

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

126

AN XY:

363051

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000247

Gnomad4 NFE exome

AF:

0.000410

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000322

AC:

AN:

111686

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

33872

show subpopulations

Gnomad4 AFR

AF:

0.0000652

Gnomad4 AMR

AF:

0.000189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000285

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000565

Gnomad4 OTH

AF:

0.000666

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000287

EpiCase

AF:

0.00104

EpiControl

AF:

0.000653

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	UBA1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2018	This variant is associated with the following publications: (PMID: 19377476) -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

UBA1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2022

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.2

DANN

Benign

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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