rs148382699

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003334.4(UBA1):c.2351G>A(p.Arg784Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000429 in 1,209,989 control chromosomes in the GnomAD database, including 3 homozygotes. There are 153 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., 69 hem., cov: 22)

Exomes 𝑓: 0.00024 ( 1 hom. 84 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.52

Publications

3 publications found

Variant links:

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

UBA1 links:

LOC105373194 (HGNC:):

LOC105373194 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050578117).

BP6

Variant X-47211112-G-A is Benign according to our data. Variant chrX-47211112-G-A is described in ClinVar as Benign. ClinVar VariationId is 513474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UBA1	NM_003334.4	MANE Select	c.2351G>A	p.Arg784Gln	missense	Exon 20 of 26	NP_003325.2
UBA1	NM_001440807.1		c.2393G>A	p.Arg798Gln	missense	Exon 21 of 27	NP_001427736.1
UBA1	NM_001440809.1		c.2369G>A	p.Arg790Gln	missense	Exon 21 of 27	NP_001427738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UBA1	ENST00000335972.11	TSL:1 MANE Select	c.2351G>A	p.Arg784Gln	missense	Exon 20 of 26	ENSP00000338413.6
UBA1	ENST00000377351.8	TSL:1	c.2351G>A	p.Arg784Gln	missense	Exon 20 of 26	ENSP00000366568.4
UBA1	ENST00000377269.3	TSL:2	c.695G>A	p.Arg232Gln	missense	Exon 4 of 10	ENSP00000366481.3

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

256

AN:

111923

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000377

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:

0.00

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.000617

AC:

113

AN:

183046

AF XY:

0.000444

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000240

AC:

263

AN:

1098015

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

AN XY:

363399

show subpopulations

African (AFR)

AF:

0.00886

AC:

234

AN:

26402

American (AMR)

AF:

0.000170

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40330

Middle Eastern (MID)

AF:

0.000725

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

842103

Other (OTH)

AF:

0.000304

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00229

AC:

256

AN:

111974

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

AN XY:

34178

show subpopulations

African (AFR)

AF:

0.00812

AC:

250

AN:

30807

American (AMR)

AF:

0.000376

AC:

AN:

10625

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2703

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6091

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53140

Other (OTH)

AF:

0.00133

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000719

Hom.:

Bravo

AF:

0.00244

ESP6500AA

AF:

0.00678

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000782

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Feb 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.016

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

5.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.3

REVEL

Benign

0.11

Sift

Benign

0.41

Sift4G

Benign

0.44

Polyphen

0.45

Vest4

0.30

MVP

0.71

MPC

1.4

ClinPred

0.021

GERP RS

4.7

Varity_R

0.67

gMVP

0.53

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over