rs5906354

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003334.4(UBA1):c.1049G>A(p.Arg350His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,199,966 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 162 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 7 hem., cov: 24)

Exomes 𝑓: 0.00047 ( 0 hom. 155 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.05

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027975082).

BP6

Variant X-47202497-G-A is Benign according to our data. Variant chrX-47202497-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 578608.

BS2

High Hemizygotes in GnomAd4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UBA1	NM_003334.4	MANE Select	c.1049G>A	p.Arg350His	missense	Exon 10 of 26	NP_003325.2
UBA1	NM_001440807.1		c.1091G>A	p.Arg364His	missense	Exon 11 of 27	NP_001427736.1
UBA1	NM_001440809.1		c.1067G>A	p.Arg356His	missense	Exon 11 of 27	NP_001427738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UBA1	ENST00000335972.11	TSL:1 MANE Select	c.1049G>A	p.Arg350His	missense	Exon 10 of 26	ENSP00000338413.6
UBA1	ENST00000377351.8	TSL:1	c.1049G>A	p.Arg350His	missense	Exon 10 of 26	ENSP00000366568.4
UBA1	ENST00000880189.1		c.1184G>A	p.Arg395His	missense	Exon 11 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes

AF:

0.000195

AC:

AN:

112841

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000931

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:

0.000225

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000147

AC:

AN:

156653

AF XY:

0.000143

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000360

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000470

AC:

511

AN:

1087125

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

155

AN XY:

355177

show subpopulations

African (AFR)

AF:

0.0000383

AC:

AN:

26142

American (AMR)

AF:

0.000297

AC:

AN:

33670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19212

East Asian (EAS)

AF:

0.0000339

AC:

AN:

29494

South Asian (SAS)

AF:

0.0000190

AC:

AN:

52679

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39515

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.000583

AC:

488

AN:

836690

Other (OTH)

AF:

0.000219

AC:

AN:

45602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000195

AC:

AN:

112841

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

AN XY:

34985

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31069

American (AMR)

AF:

0.000931

AC:

AN:

10744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3595

South Asian (SAS)

AF:

0.00

AC:

AN:

2770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6267

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000225

AC:

AN:

53299

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000129

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000663

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Infantile-onset X-linked spinal muscular atrophy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.4

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.065

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.012

MetaRNN

Benign

0.028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.11

PhyloP100

3.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

REVEL

Benign

0.051

Sift

Benign

0.57

Sift4G

Benign

0.56

Polyphen

0.0010

Vest4

0.12

MVP

0.19

MPC

0.57

ClinPred

0.022

GERP RS

-0.058

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.16

gMVP

0.47

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over