2-233672032-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_021027.3(UGT1A9):c.98T>C(p.Met33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,136 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0091 ( 11 hom., cov: 32)

Exomes 𝑓: 0.012 ( 121 hom. )

Consequence

UGT1A9
NM_021027.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.121

Variant links:

Genes affected

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:

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:

UGT1A (HGNC:12529):

UGT1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009270132).

BP6

Variant 2-233672032-T-C is Benign according to our data. Variant chr2-233672032-T-C is described in ClinVar as [Benign]. Clinvar id is 2652019.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A9	NM_021027.3 link	c.98T>C	p.Met33Thr	missense_variant	Exon 1 of 5	ENST00000354728.5	NP_066307.1	O60656-1Q5DSZ5
UGT1A10	NM_019075.4 link	c.855+34655T>C		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1	Q9HAW8-1Q5DT02
UGT1A8	NM_019076.5 link	c.855+53470T>C		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3	Q9HAW9-1Q5DSZ6
UGT1A		n.233672032T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UGT1A9	ENST00000354728.5 link	c.98T>C	p.Met33Thr	missense_variant	Exon 1 of 5	1	NM_021027.3	ENSP00000346768.4	O60656-1
UGT1A10	ENST00000344644.10 link	c.855+34655T>C		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5	Q9HAW8-1
UGT1A8	ENST00000373450.5 link	c.855+53470T>C		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4	Q9HAW9-1
UGT1A10	ENST00000373445.1 link	c.855+34655T>C		intron_variant	Intron 1 of 4	1		ENSP00000362544.1	Q9HAW8-2

Frequencies

GnomAD3 genomes

AF:

0.00907

AC:

1381

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00989

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00972

AC:

2443

AN:

251228

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0117

AC:

17139

AN:

1461830

Hom.:

121

Cov.:

AF XY:

0.0117

AC XY:

8481

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

33480

American (AMR)

AF:

0.00698

AC:

312

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00223

AC:

192

AN:

86258

European-Finnish (FIN)

AF:

0.0141

AC:

755

AN:

53416

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0136

AC:

15095

AN:

1111978

Other (OTH)

AF:

0.0112

AC:

679

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1387

2774

4161

5548

6935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00905

AC:

1379

AN:

152306

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

615

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41568

American (AMR)

AF:

0.0104

AC:

159

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00989

AC:

105

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0142

AC:

965

AN:

68016

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00648

Hom.:

Bravo

AF:

0.00867

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0128

AC:

110

ExAC

AF:

0.0109

AC:

1321

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0125

EpiControl

AF:

0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UGT1A9: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.0091

MetaRNN

Benign

0.0093

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

PhyloP100

0.12

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.065

Sift

Benign

0.70

Sift4G

Benign

0.39

Polyphen

0.096

Vest4

0.19

MPC

0.13

ClinPred

0.029

GERP RS

3.5

PromoterAI

-0.0068

Neutral

(source)

Varity_R

0.27

gMVP

0.30

Mutation Taster

=94/6

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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2-233672032-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over