rs1556786431

Variant names:

• chrX-47198878-G-A
• rs1556786431
• NM_003334.4:c.76G>A

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.76G>A​(p.Ala26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=0.13658974).

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.76G>A	p.Ala26Thr	missense	Exon 2 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.118G>A	p.Ala40Thr	missense	Exon 3 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.94G>A	p.Ala32Thr	missense	Exon 3 of 27	NP_001427738.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA1	ENST00000335972.11	TSL:1 MANE Select	c.76G>A	p.Ala26Thr	missense	Exon 2 of 26	ENSP00000338413.6	P22314-1
	UBA1	ENST00000377351.8	TSL:1	c.76G>A	p.Ala26Thr	missense	Exon 2 of 26	ENSP00000366568.4	P22314-1
	UBA1	ENST00000880189.1		c.76G>A	p.Ala26Thr	missense	Exon 2 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183498 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098245 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363599

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000237 AC: 2 AN: 842130

Other (OTH) AF: 0.00 AC: 0 AN: 46097

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.099
Sift	Benign	0.41	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.086
MVP		0.59
MPC		0.44
ClinPred		0.18	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.62
Mutation Taster		=97/3	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: rs1556786431; hg19: chrX-47058277;