X-47198883-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 12/20 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.07815507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBA1	NM_003334.4	c.81G>C	p.Gln27His	missense_variant	2/26	ENST00000335972.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBA1	ENST00000335972.11	c.81G>C	p.Gln27His	missense_variant	2/26	1	NM_003334.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112371 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34507

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

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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;.;T;T;T;T;.
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T;T;T;T;T;.;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.078	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N;.;.;.;.;N;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.020	N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.76	T;T;T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;B;.
Vest4		0.13
MutPred		0.15		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);.;.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1287237456; hg19: chrX-47058282;