rs140950898

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_003334.4(UBA1):c.1486G>A(p.Glu496Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000559 in 1,209,070 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 212 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 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. E496V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.00058 ( 0 hom. 203 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.91

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1802671).

BP6

Variant X-47203607-G-A is Benign according to our data. Variant chrX-47203607-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368337.

BS2

High Hemizygotes in GnomAd4 at 9 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBA1	NM_003334.4 link	c.1486G>A	p.Glu496Lys	missense_variant	Exon 14 of 26	ENST00000335972.11	NP_003325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
UBA1	ENST00000335972.11 link	c.1486G>A	p.Glu496Lys	missense_variant	Exon 14 of 26	1	NM_003334.4	ENSP00000338413.6
UBA1	ENST00000377351.8 link	c.1486G>A	p.Glu496Lys	missense_variant	Exon 14 of 26	1		ENSP00000366568.4
UBA1	ENST00000490869.1 link	n.375G>A		non_coding_transcript_exon_variant	Exon 4 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.000306

AC:

AN:

111000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000985

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:

0.000585

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000180

AC:

AN:

183420

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000366

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000585

AC:

642

AN:

1098070

Hom.:

Cov.:

AF XY:

0.000559

AC XY:

203

AN XY:

363424

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000747

AC:

629

AN:

841968

Other (OTH)

AF:

0.000174

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000306

AC:

AN:

111000

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

AN XY:

33154

show subpopulations

African (AFR)

AF:

0.0000985

AC:

AN:

30442

American (AMR)

AF:

0.00

AC:

AN:

10473

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000585

AC:

AN:

52978

Other (OTH)

AF:

0.00

AC:

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000414

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.000809

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

May 14, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 16, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The E496K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E496K variant is observed in 13/47,965 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. However, this variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Infantile-onset X-linked spinal muscular atrophy

Benign:2

Jan 12, 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.

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Mar 25, 2020

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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.081

T;T

LIST_S2

Uncertain

0.93

D;.

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.0

L;L

PhyloP100

4.9

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N

Sift

Benign

0.18

T;T

Sift4G

Benign

0.69

T;T

Vest4

0.31

ClinPred

0.049

GERP RS

5.3

Varity_R

0.51

gMVP

0.85

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over