NM_003334.4:c.2464+6_2464+9delGGTG

Variant names:

• chrX-47211229-AGGGT-A
• rs1175155400
• NM_003334.4:c.2464+6_2464+9delGGTG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003334.4(UBA1):​c.2464+6_2464+9delGGTG variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,206,128 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000024 (0 hom. 6 hem.)
• Consequence: UBA1 NM_003334.4 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.84

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4	c.2464+6_2464+9delGGTG		splice_region_variant, intron_variant	Intron 20 of 25	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.2464+5_2464+8delGGGT		splice_region_variant, intron_variant	Intron 20 of 25	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8	c.2464+5_2464+8delGGGT		splice_region_variant, intron_variant	Intron 20 of 25	1		ENSP00000366568.4
UBA1	ENST00000377269.3	c.808+5_808+8delGGGT		splice_region_variant, intron_variant	Intron 4 of 9	2		ENSP00000366481.3

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112158 Hom.: 0 Cov.: 22 AF XY: 0.0000291 AC XY: 1 AN XY: 34318

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000941

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000334 AC: 6 AN: 179485 Hom.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65529

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000736

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000238 AC: 26 AN: 1093970 Hom.: 0 AF XY: 0.0000166 AC XY: 6 AN XY: 361218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000309

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112158 Hom.: 0 Cov.: 22 AF XY: 0.0000291 AC XY: 1 AN XY: 34318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 05, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2464+6_2464+9delGGTG intronic variant, located in intron 19 of the UBA1 gene, results from a deletion of 4 nucleotides within intron 19 of the UBA1 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Infantile-onset X-linked spinal muscular atrophy Uncertain:1

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 20 of the UBA1 gene. It does not directly change the encoded amino acid sequence of the UBA1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with UBA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 533614). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs1175155400; hg19: chrX-47070628;