2-233760233-CATAT-CATATAT

Position:

• chr2-233760233-CATAT-CATATAT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP5 BA1

The ENST00000373409.8(UGT1A4):​c.868-6787_868-6786dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,466,600 control chromosomes in the GnomAD database, including 31,217 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,drug response,other (no stars).

• Frequency:
  • Genomes: 𝑓 0.35 (9162 hom., cov: 0)
  • Exomes 𝑓: 0.30 (22055 hom.)
• Consequence: UGT1A4 ENST00000373409.8 intron
• Clinical Significance: Conflicting classifications of pathogenicity; drug response; other criteria provided, conflicting classifications P:12 U:3 B:2 O:4
• Conservation: PhyloP100: 0.148

Genes affected

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]

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]

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]

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]

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]

UGT1A1 (HGNC:12530): (UDP glucuronosyltransferase family 1 member A1) 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 preferred substrate of this enzyme is bilirubin, although it also has moderate activity with simple phenols, flavones, and C18 steroids. Mutations in this gene result in Crigler-Najjar syndromes types I and II and in Gilbert syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP5: Variant 2-233760233-C-CAT is Pathogenic according to our data. Variant chr2-233760233-C-CAT is described in ClinVar as [Conflicting_classifications_of_pathogenicity, drug_response, other]. Clinvar id is 12275.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=9, Benign=2, other=1, Uncertain_significance=3, drug_response=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A6	NM_001072.4	c.862-6787_862-6786dup		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A4	NM_007120.3	c.868-6787_868-6786dup		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A10	NM_019075.4	c.856-6787_856-6786dup		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-6787_856-6786dup		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-6787_856-6786dup		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.868-6787_868-6786dup		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-6787_868-6786dup		intron_variant		ENST00000482026.6	NP_061966.1
UGT1A9	NM_021027.3	c.856-6787_856-6786dup		intron_variant		ENST00000354728.5	NP_066307.1
UGT1A1	NM_000463.3			upstream_gene_variant		ENST00000305208.10	NP_000454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A6	ENST00000305139.11	c.862-6787_862-6786dup		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-6787_856-6786dup		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.856-6787_856-6786dup		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A4	ENST00000373409.8	c.868-6787_868-6786dup		intron_variant		1	NM_007120.3	ENSP00000362508	P1
UGT1A5	ENST00000373414.4	c.868-6787_868-6786dup		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.856-6787_856-6786dup		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-6787_856-6786dup		intron_variant		1	NM_019076.5	ENSP00000362549	P1
UGT1A3	ENST00000482026.6	c.868-6787_868-6786dup		intron_variant		1	NM_019093.4	ENSP00000418532	P1
UGT1A1	ENST00000305208.10			upstream_gene_variant		1	NM_000463.3	ENSP00000304845	P1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52281 AN: 151044 Hom.: 9168 Cov.: 0

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.301 AC: 395737 AN: 1315438 Hom.: 22055 Cov.: 33 AF XY: 0.303 AC XY: 198308 AN XY: 653658

Gnomad4 AFR exome AF: 0.345

Gnomad4 AMR exome AF: 0.283

Gnomad4 ASJ exome AF: 0.339

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.358

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.301

GnomAD4 genome AF: 0.346 AC: 52299 AN: 151162 Hom.: 9162 Cov.: 0 AF XY: 0.348 AC XY: 25718 AN XY: 73798

Gnomad4 AFR AF: 0.398

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.319

ClinVar

Significance: Conflicting classifications of pathogenicity; drug response; other

Submissions summary: Pathogenic:12 Uncertain:3 Benign:2 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Benign:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2022	The UGT1A1 TATA box commonly has 6 TA repeats; however, there can be 5 TA repeats, 7 TA repeats, or less commonly, 8 and 9 TA repeats (Barbarino 2014). In vitro studies have shown that UGT1A1 promoter expression decreases as the number of TA repeats increases (Beutler 1998). Genotypes that are homozygous for (TA)7, homozygous for (TA)8, or compound heterozygotes for (TA)7, (TA)8, or (TA)9 cause reduced expression of UGT1A1 and are associated with Gilbert syndrome, which is characterized by increased bilirubin levels, and may have a neonatal appearance of hereditary spherocytosis (Bosma 1995, Iolascon 1998, Nikolac 2008, Ostanek 2007). Individuals who are heterozygous for the (TA)7 *28 promoter variant may have an increased risk for drug toxicity when treated with irinotecan (Marcuello 2004, Riera 2018). Individuals who are homozygous for (TA)7 or compound heterozygous for more than 6 TA repeats may experience an increased incidence of atazanavir-associated hyperbilirubinemia (Gammal 2016). References Barbarino JM et al. PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenet Genomics. 2014 24:177-183. PMID: 24492252 Beutler E et al. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 1998 95:8170-8174. PMID: 9653159 Bosma PJ et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995 333:1171-1175. PMID: 7565971 Gammal RS et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016 99:363-369. PMID: 26417955 Iolascon A et al. UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis. Blood. 1998 91:1093. PMID: 9446675 Marcuello E et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer. 2004 91:678-682. PMID: 15280927 Nikolac N et al. Rare TA repeats in promoter TATA box of the UDP glucuronosyltranferase (UGT1A1) gene in Croatian subjects. Clin Chem Lab Med. 2008 46:174-178. PMID: 18324905 Ostanek B et al. UGT1A1(TA)n promoter polymorphism--a new case of a (TA)8 allele in Caucasians. Blood Cells Mol Dis. 2007 38:78-82. PMID: 17196409 Riera P et al. Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan-induced severe toxicity. Br J Clin Pharmacol. 2018 84:1389-1392. PMID: 29504153 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 12, 2024	- -
other, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 10, 2021	- Reduced function allele
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	UGT1A1: PS3, PS4, PP4:Moderate -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This variant is located in the TATA box of the UGT1A1 promoter region. Variants altering TATA repeat length from its usual length of 6 TA repeats (aka (TA)6 or UGT1A1*1) are associated with Gilbert syndrome, a mild and often asymptomatic hyperbilirubinemia. This variant is present in population databases (rs34983651, gnomAD 40%), and has an allele count higher than expected for a pathogenic variant. This variant is known to be associated with Gilbert syndrome. Individuals who are heterozygous for this variant maintain approximately 70% of the residual enzyme activity (PMID: 7565971, 9435989, 16610035, 28520360). Individuals who are homozygous for this variant maintain approximately 30% residual enzyme activity and have elevated total bilirubin levels consistent with Gilbert syndrome (PMID: 7565971, 9435989, 11003624, 26467199). Compound heterozygosity for this variant and a pathogenic UGT1A1 coding variant may result in a more pronounced enzyme deficiency, higher total serum bilirubin levels, and a clinical presentation similar to Crigler-Najjar syndrome (PMID: 9639672, 11370628). This variant is also known as (TA)7 or UGT1A1*28. ClinVar contains an entry for this variant (Variation ID: 12275). Studies have shown that this variant alters UGT1A1 gene expression (PMID: 9639672). For these reasons, this variant has been classified as Pathogenic. -

Gilbert syndrome Pathogenic:3 Uncertain:1 Other:1

Affects, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Aug 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 12, 2022	Criteria applied: PS3,PS4,PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	This variant in the promoter region of UGT1A1 is associated with reduced transcription of UGT1A1 (Hsieh TY et al 2007). -

Crigler-Najjar syndrome, type II Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jun 19, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Lucey-Driscoll syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2009

- -

Crigler-Najjar syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS3_VeryStrong, PM4, PP4 -

Crigler-Najjar syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2020

- -

Crigler-Najjar syndrome type 1;C0017551:Gilbert syndrome;C0270210:Lucey-Driscoll syndrome;C1866173:Bilirubin, serum level of, quantitative trait locus 1;C2931132:Crigler-Najjar syndrome, type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

BS1+PS3_Supporting+PM3+PP4 -

Irinotecan response Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Apr 04, 2018

The risk of irinotecan toxicity increases with genetic variants associated with reduced UGT enzyme activity, such as UGT1A1*28. The presence of this variant results in reduced excretion of irinotecan metabolites, which leads to increased active irinotecan metabolites in the blood. Homozygous individuals (UGT1A1 *28/*28) are more likely to develop neutropenia following irinotecan therapy Poor metabolizer

Bilirubin, serum level of, quantitative trait locus 1 Other:1

association, no assertion criteria provided

literature only

OMIM

Apr 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3064744; hg19: chr2-234668879;