chr2-233760233-C-CATAT

Position:

• chr2-233760233-C-CATAT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000373409.8(UGT1A4):​c.868-6789_868-6786dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,482,566 control chromosomes in the GnomAD database, including 51 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (46 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: UGT1A4 ENST00000373409.8 intron
• Clinical Significance: Conflicting classifications of pathogenicity; drug response criteria provided, conflicting classifications P:3 U:2 B:1 O:1
• 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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2234/151212) while in subpopulation AFR AF= 0.0504 (2080/41284). AF 95% confidence interval is 0.0486. There are 46 homozygotes in gnomad4. There are 1048 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 46 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A6	NM_001072.4	c.862-6789_862-6786dup		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A4	NM_007120.3	c.868-6789_868-6786dup		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A10	NM_019075.4	c.856-6789_856-6786dup		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-6789_856-6786dup		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-6789_856-6786dup		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.868-6789_868-6786dup		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-6789_868-6786dup		intron_variant		ENST00000482026.6	NP_061966.1
UGT1A9	NM_021027.3	c.856-6789_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.862-6789_862-6786dup		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-6789_856-6786dup		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.856-6789_856-6786dup		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A4	ENST00000373409.8	c.868-6789_868-6786dup		intron_variant		1	NM_007120.3	ENSP00000362508	P1
UGT1A5	ENST00000373414.4	c.868-6789_868-6786dup		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.856-6789_856-6786dup		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-6789_856-6786dup		intron_variant		1	NM_019076.5	ENSP00000362549	P1
UGT1A3	ENST00000482026.6	c.868-6789_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: 0.0147 AC: 2219 AN: 151094 Hom.: 45 Cov.: 0

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00415

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.000485

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000738

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00253 AC: 3368 AN: 1331354 Hom.: 5 Cov.: 33 AF XY: 0.00236 AC XY: 1563 AN XY: 661668

Gnomad4 AFR exome AF: 0.0498

Gnomad4 AMR exome AF: 0.00361

Gnomad4 ASJ exome AF: 0.000760

Gnomad4 EAS exome AF: 0.000332

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.0148 AC: 2234 AN: 151212 Hom.: 46 Cov.: 0 AF XY: 0.0142 AC XY: 1048 AN XY: 73840

Gnomad4 AFR AF: 0.0504

Gnomad4 AMR AF: 0.00415

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.000485

Gnomad4 NFE AF: 0.000738

Gnomad4 OTH AF: 0.0119

ClinVar

Significance: Conflicting classifications of pathogenicity; drug response

Submissions summary: Pathogenic:3 Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 06, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 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 (no rsID available, gnomAD 5%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in trans with the c.-41_-40dup (also known as (TA)7 or UGT1A1*28) variant in individual(s) with Gilbert syndrome (PMID: 10091406, 15205079). It has also been observed to segregate with disease in related individuals. 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. This variant is also known as (TA)8, UGT1A1*37. ClinVar contains an entry for this variant (Variation ID: 549829). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant decreases UGT1A1 promoter activity (PMID: 9653159). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	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 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

UGT1A9-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The UGT1A9 c.856-6789_856-6786dupTATA variant is predicted to result in an intronic duplication. The common allele in the general population is A(TA)6TAA; therefore, this individual has two additional TA repeats in this region. The c.-43_-40dup variant found in this patient is equivalent to the A(TA)8TAA allele in the literature. One TA repeat in this region (also referred to as c.-41_-40dup or A(TA)7TAA allele) resulted in reduced expression of bilirubin UDP-glucuronosyltransferase 1 and subsequently increased serum bilirubin levels, and is considered an established risk factor for hyperbilirubinemia and Gilbert syndrome. The activity of the UGT1A1 promoter was shown to decrease with a progressively increasing number of TA repeat in one in vitro study (Beutler et al. 1998. PubMed ID: 9653159), although repeat variants other than the A(TA)7TAA allele have not been well-characterized to date. The allele frequency of the c.-43_-40dup (i.e. the A(TA)8TAA allele) was also reported at nearly 7% in the same study (Beutler et al. 1998. PubMed ID: 9653159). In the gnomAD database, the c.-43_-40dup variant was listed at a minor allele frequency of up to ~5.3% in the African population, including 12 homozygotes. In summary, although we suspect that this variant is benign in the context of severe Mendelian disease, we cannot rule out the possibility that this variant may act as a contributing risk factor for a more mild clinical presentation similar to the c.-41_-40dup risk variant. Therefore, we classify c.-43_-40dupTATA as a variant of uncertain significance in the absence of conclusive genetic and functional evidence. -

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*37. Poor metabolizer

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;