NM_003334.4:c.81G>C

Variant names:

• chrX-47198883-G-C
• rs1287237456
• NM_003334.4:c.81G>C

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.81G>C​(p.Gln27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 112,371 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: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• 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, 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=0.07815507).

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.81G>C	p.Gln27His	missense	Exon 2 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.123G>C	p.Gln41His	missense	Exon 3 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.99G>C	p.Gln33His	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.81G>C	p.Gln27His	missense	Exon 2 of 26	ENSP00000338413.6	P22314-1
	UBA1	ENST00000377351.8	TSL:1	c.81G>C	p.Gln27His	missense	Exon 2 of 26	ENSP00000366568.4	P22314-1
	UBA1	ENST00000880189.1		c.81G>C	p.Gln27His	missense	Exon 2 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112371 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112371 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34507

African (AFR) AF: 0.0000324 AC: 1 AN: 30872

American (AMR) AF: 0.00 AC: 0 AN: 10663

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3599

South Asian (SAS) AF: 0.00 AC: 0 AN: 2736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53221

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.000142 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.15
Sift	Benign	0.76	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.15		Loss of loop (P = 0.0986)
MVP		0.27
MPC		0.43
ClinPred		0.32	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.58
Mutation Taster		=99/1	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: rs1287237456; hg19: chrX-47058282;