rs143044923

Positions:

• chrX-47211069-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.33

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]

LOC105373194 (HGNC:):

ACMG classification

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	c.2308A>C	p.Asn770His	missense_variant	20/26	ENST00000335972.11
LOC105373194	XR_949047.4	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	c.2308A>C	p.Asn770His	missense_variant	20/26	1	NM_003334.4	P1
UBA1	ENST00000377351.8	c.2308A>C	p.Asn770His	missense_variant	20/26	1		P1
UBA1	ENST00000377269.3	c.652A>C	p.Asn218His	missense_variant	4/10	2

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 696 AN: 111791 Hom.: 2 Cov.: 23 AF XY: 0.00595 AC XY: 202 AN XY: 33969

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.: 2 AF XY: 0.00117 AC XY: 79 AN XY: 67552

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.: 7 Cov.: 32 AF XY: 0.000542 AC XY: 197 AN XY: 363460

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.: 2 Cov.: 23 AF XY: 0.00599 AC XY: 204 AN XY: 34030

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.: 26

Bravo AF: 0.00722

ESP6500AA AF: 0.0209 AC: 80

ESP6500EA AF: 0.000149 AC: 1

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

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	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	D;.;T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
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	T
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

Other links and lift over

dbSNP: rs143044923; hg19: chrX-47070468;