chrX-47202350-C-T

Variant names:

• chrX-47202350-C-T
• rs374197052
• NM_003334.4:c.910-8C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003334.4(UBA1):​c.910-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000869 in 1,208,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000093 (0 hom. 30 hem.)
• Consequence: UBA1 NM_003334.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002448
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0530
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• infantile-onset X-linked spinal muscular atrophy

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• inflammatory disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-47202350-C-T is Benign according to our data. Variant chrX-47202350-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 533619.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 30 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4	c.910-8C>T		splice_region_variant, intron_variant	Intron 9 of 25	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.910-8C>T		splice_region_variant, intron_variant	Intron 9 of 25	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8	c.910-8C>T		splice_region_variant, intron_variant	Intron 9 of 25	1		ENSP00000366568.4

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112106 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000974

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000449 AC: 8 AN: 178249 AF XY: 0.0000475

Gnomad AFR exome AF: 0.0000780

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000735

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000760

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000930 AC: 102 AN: 1096698 Hom.: 0 Cov.: 33 AF XY: 0.0000828 AC XY: 30 AN XY: 362168

African (AFR) AF: 0.00 AC: 0 AN: 26368

American (AMR) AF: 0.0000285 AC: 1 AN: 35117

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19358

East Asian (EAS) AF: 0.0000996 AC: 3 AN: 30123

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53807

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.000114 AC: 96 AN: 841362

Other (OTH) AF: 0.0000217 AC: 1 AN: 46013

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112106 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34266

African (AFR) AF: 0.0000974 AC: 3 AN: 30804

American (AMR) AF: 0.00 AC: 0 AN: 10619

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53135

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.93
DANN	Benign	0.72
PhyloP100		-0.053
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.042
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

Other links and lift over

dbSNP: rs374197052; hg19: chrX-47061749;