X-47210018-G-T

Variant names:

• chrX-47210018-G-T
• rs1556792871
• NM_003334.4:c.2094G>T

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.2094G>T​(p.Gln698His) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q698Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.422
• 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

LOC105373194 (HGNC:):

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=0.1416888).

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.2094G>T	p.Gln698His	missense	Exon 18 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.2136G>T	p.Gln712His	missense	Exon 19 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.2112G>T	p.Gln704His	missense	Exon 19 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.2094G>T	p.Gln698His	missense	Exon 18 of 26	ENSP00000338413.6	P22314-1
	UBA1	ENST00000377351.8	TSL:1	c.2094G>T	p.Gln698His	missense	Exon 18 of 26	ENSP00000366568.4	P22314-1
	UBA1	ENST00000880189.1		c.2229G>T	p.Gln743His	missense	Exon 19 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Infantile-onset X-linked spinal muscular atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.42
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.055
Sift	Uncertain	0.029	D
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.29		Loss of helix (P = 0.079)
MVP		0.31
MPC		0.99
ClinPred		0.73	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.29
gMVP		0.73
Mutation Taster		=65/35	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: rs1556792871; hg19: chrX-47069417;