X-47206011-A-G

Variant names:

• chrX-47206011-A-G
• rs80356546
• NM_003334.4:c.1639A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 1.94
• Publications: 10 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]

LOC105373194 (HGNC:):

INE1 (HGNC:6060): (inactivation escape 1) X chromosome inactivation provides dosage compensation for the expression level of X-linked genes from the single X in males and the two in females. This X chromosome gene is intronless and was identified because its transcription escapes X inactivation in females. This gene does not make a protein.[provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

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.1639A>G	p.Ser547Gly	missense	Exon 15 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.1681A>G	p.Ser561Gly	missense	Exon 16 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.1657A>G	p.Ser553Gly	missense	Exon 16 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.1639A>G	p.Ser547Gly	missense	Exon 15 of 26	ENSP00000338413.6
	UBA1	ENST00000377351.8	TSL:1	c.1639A>G	p.Ser547Gly	missense	Exon 15 of 26	ENSP00000366568.4
	UBA1	ENST00000490869.1	TSL:2	n.465-67A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jan 07, 2018

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1,PM2,PP5

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.22
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0050	B
Vest4		0.20
MutPred		0.88		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
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80356546; hg19: chrX-47065410;