X-47206011-A-G

Position:

• chrX-47206011-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_003334.4(UBA1):​c.1639A>G​(p.Ser547Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.94

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]

LOC105373194 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UBA1. . Gene score misZ 3.4752 (greater than the threshold 3.09). GenCC has associacion of gene with infantile-onset X-linked spinal muscular atrophy, inflammatory disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759
• PP5: Variant X-47206011-A-G is Pathogenic according to our data. Variant chrX-47206011-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 9781.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBA1	NM_003334.4	c.1639A>G	p.Ser547Gly	missense_variant	15/26	ENST00000335972.11	NP_003325.2
LOC105373194	XR_949047.4	n.278-661T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBA1	ENST00000335972.11	c.1639A>G	p.Ser547Gly	missense_variant	15/26	1	NM_003334.4	ENSP00000338413	P1
UBA1	ENST00000377351.8	c.1639A>G	p.Ser547Gly	missense_variant	15/26	1		ENSP00000366568	P1
UBA1	ENST00000490869.1	n.465-67A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D;.
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.13	A;A
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.0050	B;B
Vest4		0.20
MutPred		0.88		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.91
MPC		0.98
ClinPred		0.30	T
GERP RS		4.6
Varity_R		0.45
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80356546; hg19: chrX-47065410;