X-47198836-G-T

Variant names:

• chrX-47198836-G-T
• rs982155788
• NM_003334.4:c.34G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003334.4(UBA1):​c.34G>T​(p.Val12Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,210,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts 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. V12M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000064 (0 hom. 7 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25456858).
• BS2: High Hemizygotes in GnomAdExome4 at 7 XL,Unknown gene

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.34G>T	p.Val12Leu	missense	Exon 2 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.76G>T	p.Val26Leu	missense	Exon 3 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.52G>T	p.Val18Leu	missense	Exon 3 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.34G>T	p.Val12Leu	missense	Exon 2 of 26	ENSP00000338413.6	P22314-1
	UBA1	ENST00000377351.8	TSL:1	c.34G>T	p.Val12Leu	missense	Exon 2 of 26	ENSP00000366568.4	P22314-1
	UBA1	ENST00000880189.1		c.34G>T	p.Val12Leu	missense	Exon 2 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111952 Hom.: 0 Cov.: 24

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: 0.00000637 AC: 7 AN: 1098242 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 7 AN XY: 363596

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000712 AC: 6 AN: 842136

Other (OTH) AF: 0.0000217 AC: 1 AN: 46097

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111952 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34146

African (AFR) AF: 0.00 AC: 0 AN: 30732

American (AMR) AF: 0.00 AC: 0 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2729

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6101

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53147

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.13
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.049
Sift	Benign	0.22	T
Sift4G	Benign	0.59	T
Polyphen		0.0030	B
Vest4		0.21
MutPred		0.16		Loss of MoRF binding (P = 0.0864)
MVP		0.67
MPC		0.45
ClinPred		0.70	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.61
Mutation Taster		=84/16	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: rs982155788; hg19: chrX-47058235;