NM_003334.4:c.2626C>G

Variant names:

• chrX-47212843-C-G
• rs782749176
• NM_003334.4:c.2626C>G

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.2626C>G​(p.Pro876Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,898 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. P876S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=0.20251137).

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.2626C>G	p.Pro876Ala	missense	Exon 22 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.2668C>G	p.Pro890Ala	missense	Exon 23 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.2644C>G	p.Pro882Ala	missense	Exon 23 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.2626C>G	p.Pro876Ala	missense	Exon 22 of 26	ENSP00000338413.6	P22314-1
	UBA1	ENST00000377351.8	TSL:1	c.2626C>G	p.Pro876Ala	missense	Exon 22 of 26	ENSP00000366568.4	P22314-1
	UBA1	ENST00000880189.1		c.2761C>G	p.Pro921Ala	missense	Exon 23 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112017 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097881 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363237

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841855

Other (OTH) AF: 0.00 AC: 0 AN: 46085

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 112017 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34153

African (AFR) AF: 0.00 AC: 0 AN: 30763

American (AMR) AF: 0.00 AC: 0 AN: 10603

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3594

South Asian (SAS) AF: 0.00 AC: 0 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53192

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

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	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.091
Sift	Benign	0.064	T
Sift4G	Benign	0.11	T
Polyphen		0.014	B
Vest4		0.42
MutPred		0.55		Gain of helix (P = 0.062)
MVP		0.32
MPC		1.0
ClinPred		0.33	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.66
Mutation Taster		=92/8	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: rs782749176; hg19: chrX-47072242;