X-47211069-A-C

Position:

chrX-47211069-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_003334.4(UBA1):c.2308A>C(p.Asn770His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,209,932 control chromosomes in the GnomAD database, including 9 homozygotes. There are 401 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N770S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0063 ( 2 hom., 204 hem., cov: 23)

Exomes 𝑓: 0.00068 ( 7 hom. 197 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.012077421).

BP6

Variant X-47211069-A-C is Benign according to our data. Variant chrX-47211069-A-C is described in ClinVar as [Benign]. Clinvar id is 368343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00626 (700/111842) while in subpopulation AFR AF= 0.0218 (672/30762). AF 95% confidence interval is 0.0205. There are 2 homozygotes in gnomad4. There are 204 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4 linkuse as main transcript	c.2308A>C	p.Asn770His	missense_variant	20/26	ENST00000335972.11
LOC105373194	XR_949047.4 linkuse as main transcript	n.278-5719T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11 linkuse as main transcript	c.2308A>C	p.Asn770His	missense_variant	20/26	1	NM_003334.4	P1	P22314-1
UBA1	ENST00000377351.8 linkuse as main transcript	c.2308A>C	p.Asn770His	missense_variant	20/26	1		P1	P22314-1
UBA1	ENST00000377269.3 linkuse as main transcript	c.652A>C	p.Asn218His	missense_variant	4/10	2

Frequencies

GnomAD3 genomes

AF:

0.00623

AC:

696

AN:

111791

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

202

AN XY:

33969

show subpopulations

Gnomad AFR

AF:

0.0218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00227

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00201

GnomAD3 exomes

AF:

0.00170

AC:

312

AN:

183100

Hom.:

AF XY:

0.00117

AC XY:

AN XY:

67552

show subpopulations

Gnomad AFR exome

AF:

0.0207

Gnomad AMR exome

AF:

0.00109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.000679

AC:

746

AN:

1098090

Hom.:

Cov.:

AF XY:

0.000542

AC XY:

197

AN XY:

363460

show subpopulations

Gnomad4 AFR exome

AF:

0.0222

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000148

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000249

Gnomad4 OTH exome

AF:

0.00174

GnomAD4 genome

AF:

0.00626

AC:

700

AN:

111842

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

204

AN XY:

34030

show subpopulations

Gnomad4 AFR

AF:

0.0218

Gnomad4 AMR

AF:

0.00226

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00199

Alfa

AF:

0.000623

Hom.:

Bravo

AF:

0.00722

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00195

AC:

237

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -

Infantile-onset X-linked spinal muscular atrophy

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

UBA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.86

D;.;T

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.2

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Uncertain

0.61

Sift

Benign

0.034

D;D;D

Sift4G

Benign

0.070

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.33

MVP

0.90

MPC

2.1

ClinPred

0.036

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.86

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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