2-233757013-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007120.3(UGT1A4):​c.868-10021T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 151,034 control chromosomes in the GnomAD database, including 25,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.56 ( 25476 hom., cov: 27)

Consequence

UGT1A4
NM_007120.3 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1B:3O:1

Conservation

PhyloP100: -0.543
Variant links:
Genes affected
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]
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]
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]
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]
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]
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]
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UGT1A4NM_007120.3 linkc.868-10021T>G intron_variant Intron 1 of 4 ENST00000373409.8 NP_009051.1 P22310-1
UGT1A5NM_019078.2 linkc.868-10021T>G intron_variant Intron 1 of 4 ENST00000373414.4 NP_061951.1 P35504-1Q5DSZ9
UGT1A3NM_019093.4 linkc.868-10021T>G intron_variant Intron 1 of 4 ENST00000482026.6 NP_061966.1 P35503-1Q5DT01
UGT1A6NM_001072.4 linkc.862-10021T>G intron_variant Intron 1 of 4 ENST00000305139.11 NP_001063.2 P19224-1Q5DSZ8
UGT1A10NM_019075.4 linkc.856-10021T>G intron_variant Intron 1 of 4 ENST00000344644.10 NP_061948.1 Q9HAW8-1Q5DT02
UGT1A8NM_019076.5 linkc.856-10021T>G intron_variant Intron 1 of 4 ENST00000373450.5 NP_061949.3 Q9HAW9-1Q5DSZ6
UGT1A7NM_019077.3 linkc.856-10021T>G intron_variant Intron 1 of 4 ENST00000373426.4 NP_061950.2 Q9HAW7-1Q5DSZ7
UGT1A9NM_021027.3 linkc.856-10021T>G intron_variant Intron 1 of 4 ENST00000354728.5 NP_066307.1 O60656-1Q5DSZ5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UGT1A4ENST00000373409.8 linkc.868-10021T>G intron_variant Intron 1 of 4 1 NM_007120.3 ENSP00000362508.4 P22310-1
UGT1A5ENST00000373414.4 linkc.868-10021T>G intron_variant Intron 1 of 4 1 NM_019078.2 ENSP00000362513.3 P35504-1
UGT1A3ENST00000482026.6 linkc.868-10021T>G intron_variant Intron 1 of 4 1 NM_019093.4 ENSP00000418532.1 P35503-1
UGT1A6ENST00000305139.11 linkc.862-10021T>G intron_variant Intron 1 of 4 1 NM_001072.4 ENSP00000303174.6 P19224-1
UGT1A10ENST00000344644.10 linkc.856-10021T>G intron_variant Intron 1 of 4 1 NM_019075.4 ENSP00000343838.5 Q9HAW8-1
UGT1A9ENST00000354728.5 linkc.856-10021T>G intron_variant Intron 1 of 4 1 NM_021027.3 ENSP00000346768.4 O60656-1
UGT1A7ENST00000373426.4 linkc.856-10021T>G intron_variant Intron 1 of 4 1 NM_019077.3 ENSP00000362525.3 Q9HAW7-1
UGT1A8ENST00000373450.5 linkc.856-10021T>G intron_variant Intron 1 of 4 1 NM_019076.5 ENSP00000362549.4 Q9HAW9-1

Frequencies

GnomAD3 genomes
AF:
0.555
AC:
83744
AN:
150916
Hom.:
25430
Cov.:
27
show subpopulations
Gnomad AFR
AF:
0.820
Gnomad AMI
AF:
0.482
Gnomad AMR
AF:
0.486
Gnomad ASJ
AF:
0.538
Gnomad EAS
AF:
0.328
Gnomad SAS
AF:
0.590
Gnomad FIN
AF:
0.492
Gnomad MID
AF:
0.510
Gnomad NFE
AF:
0.438
Gnomad OTH
AF:
0.512
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.555
AC:
83838
AN:
151034
Hom.:
25476
Cov.:
27
AF XY:
0.553
AC XY:
40797
AN XY:
73738
show subpopulations
Gnomad4 AFR
AF:
0.820
Gnomad4 AMR
AF:
0.485
Gnomad4 ASJ
AF:
0.538
Gnomad4 EAS
AF:
0.327
Gnomad4 SAS
AF:
0.589
Gnomad4 FIN
AF:
0.492
Gnomad4 NFE
AF:
0.438
Gnomad4 OTH
AF:
0.512
Alfa
AF:
0.460
Hom.:
22876
Bravo
AF:
0.564
Asia WGS
AF:
0.466
AC:
1621
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Gilbert syndrome Pathogenic:3
-
Centogene AG - the Rare Disease Company
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2019
Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control

- -

Aug 12, 2022
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS3,PS4,PM3 -

not provided Benign:2
Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

UGT1A10: BS1, BS2; UGT1A3: BS1, BS2; UGT1A4: BS1, BS2; UGT1A5: BS1, BS2; UGT1A6: BS1, BS2; UGT1A7: BS1, BS2; UGT1A8: BS1, BS2; UGT1A9: BS1, BS2 -

Aug 19, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

UGT1A8-related condition Pathogenic:1
Jul 07, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Crigler-Najjar syndrome type 1;C0270210:Lucey-Driscoll syndrome;C2931132:Crigler-Najjar syndrome, type II Uncertain:1
-
Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

UGT1A9-related disorder Benign:1
Jan 16, 2023
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Gilbert syndrome, susceptibility to Other:1
Nov 01, 2004
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
CADD
Benign
3.7
DANN
Benign
0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4124874; hg19: chr2-234665659; API