NM_003334.4:c.1486G>A

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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
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

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.1486G>A	p.Glu496Lys	missense	Exon 14 of 26	NP_003325.2
UBA1	NM_001440807.1		c.1528G>A	p.Glu510Lys	missense	Exon 15 of 27	NP_001427736.1
UBA1	NM_001440809.1		c.1504G>A	p.Glu502Lys	missense	Exon 15 of 27	NP_001427738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBA1	ENST00000335972.11	TSL:1 MANE Select	c.1486G>A	p.Glu496Lys	missense	Exon 14 of 26	ENSP00000338413.6	P22314-1
UBA1	ENST00000377351.8	TSL:1	c.1486G>A	p.Glu496Lys	missense	Exon 14 of 26	ENSP00000366568.4	P22314-1
UBA1	ENST00000880189.1		c.1621G>A	p.Glu541Lys	missense	Exon 15 of 27	ENSP00000550248.1

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:

ALSPAC

AF:

0.000346

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Infantile-onset X-linked spinal muscular atrophy (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.0

PhyloP100

4.9

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

REVEL

Benign

0.10

Sift

Benign

0.18

Sift4G

Benign

0.69

Polyphen

0.056

Vest4

0.31

MVP

0.81

MPC

1.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over