NM_003334.4:c.2622C>A

Variant names:

• chrX-47212839-C-A
• rs1556793890
• NM_003334.4:c.2622C>A

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.2622C>A​(p.Asp874Glu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D874A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.95
• 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, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• 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=0.18040699).

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.2622C>A	p.Asp874Glu	missense	Exon 22 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.2664C>A	p.Asp888Glu	missense	Exon 23 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.2640C>A	p.Asp880Glu	missense	Exon 23 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.2622C>A	p.Asp874Glu	missense	Exon 22 of 26	ENSP00000338413.6
	UBA1	ENST00000377351.8	TSL:1	c.2622C>A	p.Asp874Glu	missense	Exon 22 of 26	ENSP00000366568.4
	UBA1	ENST00000377269.3	TSL:2	c.966C>A	p.Asp322Glu	missense	Exon 6 of 10	ENSP00000366481.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	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	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.65	N
PhyloP100		2.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.14
Sift	Benign	0.74	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.38
MutPred		0.69		Gain of disorder (P = 0.1265)
MVP		0.39
MPC		0.98
ClinPred		0.37	T
GERP RS		1.1
Varity_R		0.28
gMVP		0.70
Mutation Taster		=62/38	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: rs1556793890; hg19: chrX-47072238;