NM_003334.4:c.574C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_003334.4(UBA1):c.574C>T(p.Arg192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,197,425 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts 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. R192Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000030 ( 0 hom. 14 hem. )

Consequence

UBA1
NM_003334.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.237

Publications

1 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.35817844).

BP6

Variant X-47200987-C-T is Benign according to our data. Variant chrX-47200987-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533611.

BS2

High Hemizygotes 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.574C>T	p.Arg192Trp	missense	Exon 6 of 26	NP_003325.2
UBA1	NM_001440807.1		c.616C>T	p.Arg206Trp	missense	Exon 7 of 27	NP_001427736.1
UBA1	NM_001440809.1		c.592C>T	p.Arg198Trp	missense	Exon 7 of 27	NP_001427738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UBA1	ENST00000335972.11	TSL:1 MANE Select	c.574C>T	p.Arg192Trp	missense	Exon 6 of 26	ENSP00000338413.6
UBA1	ENST00000377351.8	TSL:1	c.574C>T	p.Arg192Trp	missense	Exon 6 of 26	ENSP00000366568.4
UBA1	ENST00000880189.1		c.709C>T	p.Arg237Trp	missense	Exon 7 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112117

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000562

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000697

AC:

AN:

157811

AF XY:

0.0000599

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000791

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000566

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000147

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000304

AC:

AN:

1085308

Hom.:

Cov.:

AF XY:

0.0000396

AC XY:

AN XY:

353460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26146

American (AMR)

AF:

0.0000591

AC:

AN:

33817

Ashkenazi Jewish (ASJ)

AF:

0.0000523

AC:

AN:

19125

East Asian (EAS)

AF:

0.000270

AC:

AN:

29628

South Asian (SAS)

AF:

0.0000769

AC:

AN:

52043

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39719

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4046

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

835173

Other (OTH)

AF:

0.0000658

AC:

AN:

45611

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

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:

0.0000446

AC:

AN:

112117

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34289

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30811

American (AMR)

AF:

0.00

AC:

AN:

10645

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.000562

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6159

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53102

Other (OTH)

AF:

0.00

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000498

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000666

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

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

FATHMM_MKL

Benign

0.22

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.0

PhyloP100

-0.24

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.2

REVEL

Benign

0.26

Sift

Uncertain

0.014

Sift4G

Uncertain

0.011

Polyphen

0.81

Vest4

0.57

MutPred

0.71

Loss of methylation at R192 (P = 0.0479)

MVP

0.55

MPC

1.3

ClinPred

0.35

GERP RS

-0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.93

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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