NM_003334.4:c.1-555A>T

Variant names:

• chrX-47198248-A-T
• rs4468050
• NM_003334.4:c.1-555A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003334.4(UBA1):​c.1-555A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000115 in 869,412 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000012 (0 hom. 1 hem.)
• Consequence: UBA1 NM_003334.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.641
• Publications: 7 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• inflammatory disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08523613).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA1	NM_003334.4	MANE Select	c.1-555A>T		intron	N/A	NP_003325.2
	UBA1	NM_001440807.1		c.-5-61A>T		intron	N/A	NP_001427736.1
	UBA1	NM_001440809.1		c.19-555A>T		intron	N/A	NP_001427738.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA1	ENST00000335972.11	TSL:1 MANE Select	c.1-555A>T		intron	N/A	ENSP00000338413.6	P22314-1
	UBA1	ENST00000377351.8	TSL:1	c.1-555A>T		intron	N/A	ENSP00000366568.4	P22314-1
	UBA1	ENST00000451702.2	TSL:5	c.46A>T	p.Ile16Phe	missense	Exon 1 of 6	ENSP00000401101.1	Q5JRS2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000115 AC: 1 AN: 869412 Hom.: 0 Cov.: 42 AF XY: 0.00000354 AC XY: 1 AN XY: 282298

African (AFR) AF: 0.00 AC: 0 AN: 19305

American (AMR) AF: 0.00 AC: 0 AN: 22247

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11947

East Asian (EAS) AF: 0.00 AC: 0 AN: 9708

South Asian (SAS) AF: 0.0000210 AC: 1 AN: 47688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 702699

Other (OTH) AF: 0.00 AC: 0 AN: 31802

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 16097

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.070
DANN	Benign	0.36
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.66	T
PhyloP100		-0.64
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
MutPred		0.16		Loss of methylation at K20 (P = 0.1182)
MVP		0.26
ClinPred		0.073	T
GERP RS		-3.1
Mutation Taster		=100/0	polymorphism

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: rs4468050; hg19: chrX-47057647;