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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4 link	c.1049G>A	p.Arg350His	missense_variant	Exon 10 of 26	ENST00000335972.11	NP_003325.2	P22314-1A0A024R1A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBA1	ENST00000335972.11 link	c.1049G>A	p.Arg350His	missense_variant	Exon 10 of 26	1	NM_003334.4	ENSP00000338413.6	P22314-1
UBA1	ENST00000377351.8 link	c.1049G>A	p.Arg350His	missense_variant	Exon 10 of 26	1		ENSP00000366568.4	P22314-1
UBA1	ENST00000490869.1 link	n.-196G>A		upstream_gene_variant		2

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Infantile-onset X-linked spinal muscular atrophy

Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 350 of the UBA1 protein (p.Arg350His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with UBA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578608). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Dec 16, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jan 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.11

N;N

PhyloP100

3.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.051

Sift

Benign

0.57

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0010

B;B

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over