chr2-233729259-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_019093.4(UGT1A3):c.133C>T(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,614,078 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0022 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 81 hom. )

Consequence

UGT1A3
NM_019093.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.10

Publications

27 publications found

Variant links:

Genes affected

UGT1A3 (HGNC:12535): (UDP glucuronosyltransferase family 1 member A3) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. Substrates of this enzyme include estrone, 2-hydroxyestrone, and metabolites of benzo alpha-pyrene. [provided by RefSeq, Jul 2008]

UGT1A3 links:

UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [provided by RefSeq, Jul 2008]

UGT1A4 links:

UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. [provided by RefSeq, Jul 2008]

UGT1A5 links:

UGT1A6 (HGNC:12538): (UDP glucuronosyltransferase family 1 member A6) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants. [provided by RefSeq, Jul 2008]

UGT1A6 links:

UGT1A10 (HGNC:12531): (UDP glucuronosyltransferase family 1 member A10) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity on mycophenolic acid, coumarins, and quinolines. [provided by RefSeq, Jul 2008]

UGT1A10 links:

UGT1A8 (HGNC:12540): (UDP glucuronosyltransferase family 1 member A8) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]

UGT1A8 links:

UGT1A7 (HGNC:12539): (UDP glucuronosyltransferase family 1 member A7) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has moderate glucuronidase activity with phenols. [provided by RefSeq, Jul 2008]

UGT1A7 links:

UGT1A9 (HGNC:12541): (UDP glucuronosyltransferase family 1 member A9) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenols. [provided by RefSeq, Jul 2008]

UGT1A9 links:

UGT1A (HGNC:12529):

UGT1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005053729).

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
UGT1A3	NM_019093.4 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 1 of 5	ENST00000482026.6	NP_061966.1
UGT1A4	NM_007120.3 link	c.867+9572C>T		intron_variant	Intron 1 of 4	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2 link	c.867+15401C>T		intron_variant	Intron 1 of 4	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4 link	c.861+35394C>T		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4 link	c.856-37775C>T		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5 link	c.856-37775C>T		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3 link	c.856-37775C>T		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3 link	c.856-37775C>T		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
UGT1A3	ENST00000482026.6 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 1 of 5	1	NM_019093.4	ENSP00000418532.1
UGT1A4	ENST00000373409.8 link	c.867+9572C>T		intron_variant	Intron 1 of 4	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4 link	c.867+15401C>T		intron_variant	Intron 1 of 4	1	NM_019078.2	ENSP00000362513.3
UGT1A6	ENST00000305139.11 link	c.861+35394C>T		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10 link	c.856-37775C>T		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5 link	c.856-37775C>T		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4 link	c.856-37775C>T		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5 link	c.856-37775C>T		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

337

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0416

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00444

AC:

1117

AN:

251446

AF XY:

0.00420

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.0395

Gnomad FIN exome

AF:

0.00564

Gnomad NFE exome

AF:

0.000536

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00223

AC:

3264

AN:

1461750

Hom.:

Cov.:

106

AF XY:

0.00233

AC XY:

1695

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33470

American (AMR)

AF:

0.00197

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00276

AC:

AN:

26130

East Asian (EAS)

AF:

0.0531

AC:

2107

AN:

39700

South Asian (SAS)

AF:

0.00307

AC:

265

AN:

86256

European-Finnish (FIN)

AF:

0.00466

AC:

249

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000286

AC:

318

AN:

1111896

Other (OTH)

AF:

0.00267

AC:

161

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

212

423

635

846

1058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00221

AC:

337

AN:

152328

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41578

American (AMR)

AF:

0.000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0417

AC:

216

AN:

5182

South Asian (SAS)

AF:

0.00373

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00101

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.000539

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00427

AC:

518

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.82

LIST_S2

Benign

0.068

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.3

PhyloP100

-1.1

PROVEAN

Uncertain

-4.3

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.51

ClinPred

0.093

GERP RS

-3.5

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.37

gMVP

0.50

Mutation Taster

=93/7

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

Computational scores

Splicing

Publications

Other links and lift over