X-47200987-C-A

Variant names:

• chrX-47200987-C-A
• rs185589110
• NM_003334.4:c.574C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003334.4(UBA1):​c.574C>A​(p.Arg192Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,197,475 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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 0.000036 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 5 hem.)
• Consequence: UBA1 NM_003334.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.237
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant X-47200987-C-A is Benign according to our data. Variant chrX-47200987-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 465036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.237 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 3 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA1	NM_003334.4	MANE Select	c.574C>A	p.Arg192Arg	synonymous	Exon 6 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.616C>A	p.Arg206Arg	synonymous	Exon 7 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.592C>A	p.Arg198Arg	synonymous	Exon 7 of 27	NP_001427738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA1	ENST00000335972.11	TSL:1 MANE Select	c.574C>A	p.Arg192Arg	synonymous	Exon 6 of 26	ENSP00000338413.6
	UBA1	ENST00000377351.8	TSL:1	c.574C>A	p.Arg192Arg	synonymous	Exon 6 of 26	ENSP00000366568.4
	UBA1	ENST00000442035.5	TSL:5	c.616C>A	p.Arg206Arg	synonymous	Exon 7 of 9	ENSP00000389583.1

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112117 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

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: 0.0000190 AC: 3 AN: 157811 AF XY: 0.0000399

Gnomad AFR exome AF: 0.000269

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 12 AN: 1085306 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 5 AN XY: 353458

African (AFR) AF: 0.000421 AC: 11 AN: 26146

American (AMR) AF: 0.00 AC: 0 AN: 33817

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19125

East Asian (EAS) AF: 0.00 AC: 0 AN: 29628

South Asian (SAS) AF: 0.0000192 AC: 1 AN: 52043

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39719

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4046

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835172

Other (OTH) AF: 0.00 AC: 0 AN: 45610

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 112169 Hom.: 0 Cov.: 23 AF XY: 0.0000873 AC XY: 3 AN XY: 34351

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000972 AC: 3 AN: 30880

American (AMR) AF: 0.0000938 AC: 1 AN: 10658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2753

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6159

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53095

Other (OTH) AF: 0.00 AC: 0 AN: 1526

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Infantile-onset X-linked spinal muscular atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.5
DANN	Benign	0.68
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs185589110; hg19: chrX-47060386;