2-233760233-CATAT-CAT

Position:

• chr2-233760233-CATAT-CAT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_007120.3(UGT1A4):​c.868-6787_868-6786delTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,449,924 control chromosomes in the GnomAD database, including 210 homozygotes. Variant has been reported in ClinVar as Benign,drug response (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (101 hom., cov: 0)
  • Exomes 𝑓: 0.0047 (109 hom.)
• Consequence: UGT1A4 NM_007120.3 intron
• Clinical Significance: Benign; drug response criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.148

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]

UGT1A (HGNC:):

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A4	NM_007120.3	c.868-6787_868-6786delTA		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.868-6787_868-6786delTA		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-6787_868-6786delTA		intron_variant		ENST00000482026.6	NP_061966.1
UGT1A6	NM_001072.4	c.862-6787_862-6786delTA		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-6787_856-6786delTA		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-6787_856-6786delTA		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-6787_856-6786delTA		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.856-6787_856-6786delTA		intron_variant		ENST00000354728.5	NP_066307.1
UGT1A1	NM_000463.3	c.-54_-53delAT		upstream_gene_variant		ENST00000305208.10	NP_000454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8	c.868-6787_868-6786delTA		intron_variant		1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.868-6787_868-6786delTA		intron_variant		1	NM_019078.2	ENSP00000362513.3
UGT1A3	ENST00000482026.6	c.868-6787_868-6786delTA		intron_variant		1	NM_019093.4	ENSP00000418532.1
UGT1A6	ENST00000305139.11	c.862-6787_862-6786delTA		intron_variant		1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-6787_856-6786delTA		intron_variant		1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.856-6787_856-6786delTA		intron_variant		1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.856-6787_856-6786delTA		intron_variant		1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-6787_856-6786delTA		intron_variant		1	NM_019076.5	ENSP00000362549.4
UGT1A1	ENST00000305208.10	c.-54_-53delAT		upstream_gene_variant		1	NM_000463.3	ENSP00000304845.5

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3345 AN: 151090 Hom.: 101 Cov.: 0

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00804

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000582

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.0149

GnomAD4 exome AF: 0.00474 AC: 6158 AN: 1298716 Hom.: 109 AF XY: 0.00447 AC XY: 2878 AN XY: 644540

Gnomad4 AFR exome AF: 0.0816

Gnomad4 AMR exome AF: 0.00740

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.00237

Gnomad4 NFE exome AF: 0.00276

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.0222 AC: 3351 AN: 151208 Hom.: 101 Cov.: 0 AF XY: 0.0204 AC XY: 1504 AN XY: 73832

Gnomad4 AFR AF: 0.0733

Gnomad4 AMR AF: 0.00803

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000582

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.0148

Alfa AF: 0.00175 Hom.: 268

ClinVar

Significance: Benign; drug response

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

UGT1A9-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2022

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). -

Irinotecan response Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Apr 04, 2018

UGT1A1*36 is not associated with irinotecan toxicity. This variant is associated with increased promoter activity and a reduced risk of neonatal hyperbilirubinemia. Normal metabolizer

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs3064744; hg19: chr2-234668879;