X-47202496-C-A

Variant names:

• chrX-47202496-C-A
• rs1556788657
• NM_003334.4:c.1048C>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.1048C>A​(p.Arg350Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,087,260 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• 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: 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: 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=0.11128026).

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.1048C>A	p.Arg350Ser	missense	Exon 10 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.1090C>A	p.Arg364Ser	missense	Exon 11 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.1066C>A	p.Arg356Ser	missense	Exon 11 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.1048C>A	p.Arg350Ser	missense	Exon 10 of 26	ENSP00000338413.6
	UBA1	ENST00000377351.8	TSL:1	c.1048C>A	p.Arg350Ser	missense	Exon 10 of 26	ENSP00000366568.4
	UBA1	ENST00000490869.1	TSL:2	n.-197C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1087260 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 355206

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

African (AFR) AF: 0.00 AC: 0 AN: 26133

American (AMR) AF: 0.00 AC: 0 AN: 33736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19216

East Asian (EAS) AF: 0.0000339 AC: 1 AN: 29471

South Asian (SAS) AF: 0.00 AC: 0 AN: 52674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836772

Other (OTH) AF: 0.00 AC: 0 AN: 45617

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.038
Sift	Benign	0.40	T
Sift4G	Benign	0.40	T
Polyphen		0.042	B
Vest4		0.25
MutPred		0.28		Gain of phosphorylation at R350 (P = 0.0247)
MVP		0.24
MPC		0.52
ClinPred		0.58	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.74
gMVP		0.64
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1556788657; hg19: chrX-47061895;