rs143935711

chrX-47202718-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003334.4(UBA1):c.1137C>T(p.Asp379=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,210,284 control chromosomes in the GnomAD database, including 6 homozygotes. There are 187 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 0.00052 (0 hom., 13 hem., cov: 24)
  • Exomes 𝑓: 0.00045 (6 hom. 174 hem.)
• Consequence: UBA1 NM_003334.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-47202718-C-T is Benign according to our data. Variant chrX-47202718-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 368333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47202718-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000455 (499/1097387) while in subpopulation MID AF= 0.0247 (102/4132). AF 95% confidence interval is 0.0208. There are 6 homozygotes in gnomad4_exome. There are 174 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.1137C>T	p.Asp379=	synonymous_variant	11/26	ENST00000335972.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.1137C>T	p.Asp379=	synonymous_variant	11/26	1	NM_003334.4	P1
UBA1	ENST00000377351.8	c.1137C>T	p.Asp379=	synonymous_variant	11/26	1		P1
UBA1	ENST00000490869.1	n.26C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.000523 AC: 59 AN: 112842 Hom.: 0 Cov.: 24 AF XY: 0.000372 AC XY: 13 AN XY: 34980

Gnomad AFR AF: 0.0000644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00527

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000722

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.000637

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000581 AC: 105 AN: 180678 Hom.: 0 AF XY: 0.000444 AC XY: 29 AN XY: 65348

Gnomad AFR exome AF: 0.0000771

Gnomad AMR exome AF: 0.000624

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000698

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000472

Gnomad OTH exome AF: 0.00291

GnomAD4 exome AF: 0.000455 AC: 499 AN: 1097387 Hom.: 6 Cov.: 33 AF XY: 0.000480 AC XY: 174 AN XY: 362755

Gnomad4 AFR exome AF: 0.000227

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00372

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000760

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.000803

GnomAD4 genome AF: 0.000523 AC: 59 AN: 112897 Hom.: 0 Cov.: 24 AF XY: 0.000371 AC XY: 13 AN XY: 35045

Gnomad4 AFR AF: 0.0000642

Gnomad4 AMR AF: 0.000279

Gnomad4 ASJ AF: 0.00527

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000724

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000638

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00122 Hom.: 6

Bravo AF: 0.000521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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 25, 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 provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	UBA1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.38
Dann	Benign	0.69
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

Other links and lift over

dbSNP: rs143935711; hg19: chrX-47062117; COSMIC: COSV60115239; COSMIC: COSV60115239;