rs2230147

Positions:

• chrX-47210862-G-A
• chrX-47210862-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003334.4(UBA1):​c.2220G>A​(p.Pro740=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,209,034 control chromosomes in the GnomAD database, including 1,785 homozygotes. There are 5,067 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (923 hom., 2445 hem., cov: 22)
  • Exomes 𝑓: 0.0087 (862 hom. 2622 hem.)
• Consequence: UBA1 NM_003334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.28

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-47210862-G-A is Benign according to our data. Variant chrX-47210862-G-A is described in ClinVar as [Benign]. Clinvar id is 368342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47210862-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.2220G>A	p.Pro740=	synonymous_variant	19/26	ENST00000335972.11
LOC105373194	XR_949047.4	n.278-5512C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.2220G>A	p.Pro740=	synonymous_variant	19/26	1	NM_003334.4	P1
UBA1	ENST00000377351.8	c.2220G>A	p.Pro740=	synonymous_variant	19/26	1		P1
UBA1	ENST00000377269.3	c.564G>A	p.Pro188=	synonymous_variant	3/10	2

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 9036 AN: 111280 Hom.: 917 Cov.: 22 AF XY: 0.0723 AC XY: 2422 AN XY: 33498

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.00302

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0212

Gnomad NFE AF: 0.000980

Gnomad OTH AF: 0.0656

GnomAD3 exomes AF: 0.0229 AC: 4140 AN: 181091 Hom.: 443 AF XY: 0.0144 AC XY: 948 AN XY: 65691

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000748

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.00916

GnomAD4 exome AF: 0.00875 AC: 9603 AN: 1097700 Hom.: 862 Cov.: 32 AF XY: 0.00722 AC XY: 2622 AN XY: 363092

Gnomad4 AFR exome AF: 0.287

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.00175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.0815 AC: 9077 AN: 111334 Hom.: 923 Cov.: 22 AF XY: 0.0729 AC XY: 2445 AN XY: 33562

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.0333

Gnomad4 ASJ AF: 0.00302

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000748

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000980

Gnomad4 OTH AF: 0.0648

Alfa AF: 0.0120 Hom.: 275

Bravo AF: 0.0940

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0020
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230147; hg19: chrX-47070261;