rs80356547

Variant names:

• chrX-47206103-C-T
• rs80356547
• NM_003334.4:c.1731C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_003334.4(UBA1):​c.1731C>T​(p.Asn577Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: UBA1 NM_003334.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:1 O:1
• Conservation: PhyloP100: -2.12
• 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]

LOC105373194 (HGNC:):

INE1 (HGNC:6060): (inactivation escape 1) X chromosome inactivation provides dosage compensation for the expression level of X-linked genes from the single X in males and the two in females. This X chromosome gene is intronless and was identified because its transcription escapes X inactivation in females. This gene does not make a protein.[provided by RefSeq, May 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4	c.1731C>T	p.Asn577Asn	synonymous_variant	Exon 15 of 26	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.1731C>T	p.Asn577Asn	synonymous_variant	Exon 15 of 26	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8	c.1731C>T	p.Asn577Asn	synonymous_variant	Exon 15 of 26	1		ENSP00000366568.4
UBA1	ENST00000490869.1	n.490C>T		non_coding_transcript_exon_variant	Exon 5 of 6	2
INE1	ENST00000456273.1	n.*238C>T		downstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1088017 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 355411

African (AFR) AF: 0.00 AC: 0 AN: 26173

American (AMR) AF: 0.00 AC: 0 AN: 34020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19230

East Asian (EAS) AF: 0.00 AC: 0 AN: 29722

South Asian (SAS) AF: 0.00 AC: 0 AN: 52416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836810

Other (OTH) AF: 0.00 AC: 0 AN: 45714

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy Pathogenic:2 Other:1

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This synonymous variant has been previously reported as a hemizygous and de novo change in multiple unrelated males with X-linked spinal muscular atrophy (SMAX2) (MIM: #301830, PMID: 18179898, 26028276, 8528211). Analysis of blood cells from an affected individual harboring this variant demonstrated reduced UBA1 expression relative to healthy controls (PMID: 18179898). Bisulfite sequencing demonstrated that the c.1731C>T variant resulted in the loss of one CpG dinucleotide methylation site within a CpG island of 13 methylation sites located in exon 15 (PMID: 18179898). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1731C>T (p.Asn577Asn) variant is classified as Pathogenic. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Benign:1

Jul 11, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.36
CADD	Benign	2.2
DANN	Benign	0.93
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	disease causing (ClinVar)

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: rs80356547; hg19: chrX-47065502; COSMIC: COSV60112920; COSMIC: COSV60112920;