Genetic Variant UXS1:p.Arg201His (chr2-106125655-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001253875.2(UXS1):c.602G>A(p.Arg201His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,579,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

UXS1
NM_001253875.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

Publications

3 publications found

Variant links:

Genes affected

UXS1 (HGNC:17729): (UDP-glucuronate decarboxylase 1) This gene encodes an enzyme found in the perinuclear Golgi which catalyzes the synthesis of UDP-xylose used in glycosaminoglycan (GAG) synthesis on proteoglycans. The GAG chains are covalently attached to proteoglycans which participate in signaling pathways during development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

UXS1 Gene-Disease associations (from GenCC):

skeletal dysplasia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

UXS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

BS2

High AC in GnomAdExome4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001253875.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UXS1	NM_001253875.2	MANE Select	c.602G>A	p.Arg201His	missense	Exon 8 of 15	NP_001240804.1	Q8NBZ7-2
UXS1	NM_025076.5		c.587G>A	p.Arg196His	missense	Exon 8 of 15	NP_079352.2
UXS1	NM_001377504.1		c.602G>A	p.Arg201His	missense	Exon 8 of 13	NP_001364433.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UXS1	ENST00000283148.12	TSL:2 MANE Select	c.602G>A	p.Arg201His	missense	Exon 8 of 15	ENSP00000283148.7	Q8NBZ7-2
UXS1	ENST00000409501.7	TSL:1	c.587G>A	p.Arg196His	missense	Exon 8 of 15	ENSP00000387019.3	Q8NBZ7-1
UXS1	ENST00000409032.5	TSL:1	c.83G>A	p.Arg28His	missense	Exon 3 of 10	ENSP00000387096.1	Q8NBZ7-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

196742

AF XY:

0.0000191

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000347

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.0000711

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1427254

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

706448

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32670

American (AMR)

AF:

0.00

AC:

AN:

39886

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25476

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37872

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000320

AC:

AN:

1094372

Other (OTH)

AF:

0.0000169

AC:

AN:

59188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000731

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000167

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

PhyloP100

7.4

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.78

MutPred

0.76

Loss of MoRF binding (P = 0.0071)

MVP

0.93

MPC

1.8

ClinPred

1.0

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.86

Mutation Taster

=40/60

disease causing

(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