chrX-47201619-C-G

Variant names:

• chrX-47201619-C-G
• rs4239964
• NM_003334.4:c.811+9C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_003334.4(UBA1):​c.811+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (37872 hom., 32775 hem., cov: 23)
  • Exomes 𝑓: 0.98 (355394 hom. 356236 hem.)
  • Failed GnomAD Quality Control
• Consequence: UBA1 NM_003334.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.363
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant X-47201619-C-G is Benign according to our data. Variant chrX-47201619-C-G is described in ClinVar as Benign. ClinVar VariationId is 368331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4	c.811+9C>G		intron_variant	Intron 8 of 25	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.811+9C>G		intron_variant	Intron 8 of 25	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8	c.811+9C>G		intron_variant	Intron 8 of 25	1		ENSP00000366568.4
UBA1	ENST00000442035.5	c.*9C>G		downstream_gene_variant		5		ENSP00000389583.1
UBA1	ENST00000412206.5	c.*8C>G		downstream_gene_variant		5		ENSP00000415033.1

Frequencies

GnomAD3 genomes AF: 0.986 AC: 109502 AN: 111040 Hom.: 37880 Cov.: 23

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.990

Gnomad ASJ AF: 0.980

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.984

Gnomad OTH AF: 0.983

GnomAD2 exomes AF: 0.980 AC: 178301 AN: 182014 AF XY: 0.976

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.981

Gnomad EAS exome AF: 0.953

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.984

Gnomad OTH exome AF: 0.978

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.983 AC: 1078778 AN: 1097948 Hom.: 355394 Cov.: 45 AF XY: 0.980 AC XY: 356236 AN XY: 363330

African (AFR) AF: 0.998 AC: 26341 AN: 26400

American (AMR) AF: 0.992 AC: 34924 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 19031 AN: 19383

East Asian (EAS) AF: 0.972 AC: 29365 AN: 30205

South Asian (SAS) AF: 0.934 AC: 50516 AN: 54100

European-Finnish (FIN) AF: 0.994 AC: 40282 AN: 40521

Middle Eastern (MID) AF: 0.974 AC: 3990 AN: 4095

European-Non Finnish (NFE) AF: 0.985 AC: 829235 AN: 841967

Other (OTH) AF: 0.979 AC: 45094 AN: 46083

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.986 AC: 109552 AN: 111094 Hom.: 37872 Cov.: 23 AF XY: 0.986 AC XY: 32775 AN XY: 33256

African (AFR) AF: 0.997 AC: 30387 AN: 30481

American (AMR) AF: 0.990 AC: 10382 AN: 10485

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 2588 AN: 2641

East Asian (EAS) AF: 0.953 AC: 3346 AN: 3510

South Asian (SAS) AF: 0.935 AC: 2418 AN: 2585

European-Finnish (FIN) AF: 0.996 AC: 5918 AN: 5944

Middle Eastern (MID) AF: 0.986 AC: 214 AN: 217

European-Non Finnish (NFE) AF: 0.984 AC: 52203 AN: 53040

Other (OTH) AF: 0.978 AC: 1480 AN: 1513

Alfa AF: 0.980 Hom.: 8268

Bravo AF: 0.987

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied by a panel of primary immunodeficiencies. Number of patients: 93. Only high quality variants are reported. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Nov 16, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.7
DANN	Benign	0.50
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4239964; hg19: chrX-47061018;