2-233760233-CATAT-CATATATAT

Variant names:

• chr2-233760233-C-CATAT
• rs3064744
• NM_007120.3:c.868-6789_868-6786dupTATA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PS3 BS1 BS2

The NM_007120.3(UGT1A4):​c.868-6789_868-6786dupTATA 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). ClinVar reports functional evidence for this variant: "SCV002161949: Experimental studies have shown that this variant decreases UGT1A1 promoter activity (PMID:9653159)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (46 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: UGT1A4 NM_007120.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity; drug response criteria provided, conflicting classifications P:4 U:2 B:1 O:1
• Conservation: PhyloP100: 0.148
• Publications: 57 publications found

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:12529):

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]

UGT1A1 Gene-Disease associations (from GenCC):

• Crigler-Najjar syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Orphanet, G2P
• Crigler-Najjar syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Gilbert syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002161949: Experimental studies have shown that this variant decreases UGT1A1 promoter activity (PMID: 9653159).; SCV003799419: In vitro studies have shown that UGT1A1 promoter expression decreases as the number of TA repeats increases (Beutler 1998). PMID: 9653159; SCV005888469: The most pronounced variant effect results in 33% of normal activity in an in vitro cellular assay (Iolascon_1999, Beutler_1998). PMID:9653159, 15205079, 10091406, 16269258, 35527687
• 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A4	NM_007120.3	MANE Select	c.868-6789_868-6786dupTATA		intron	N/A	NP_009051.1	P22310-1
	UGT1A5	NM_019078.2	MANE Select	c.868-6789_868-6786dupTATA		intron	N/A	NP_061951.1	Q5DSZ9
	UGT1A3	NM_019093.4	MANE Select	c.868-6789_868-6786dupTATA		intron	N/A	NP_061966.1	Q5DT01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A4	ENST00000373409.8	TSL:1 MANE Select	c.868-6801_868-6800insATAT		intron	N/A	ENSP00000362508.4	P22310-1
	UGT1A5	ENST00000373414.4	TSL:1 MANE Select	c.868-6801_868-6800insATAT		intron	N/A	ENSP00000362513.3	P35504-1
	UGT1A3	ENST00000482026.6	TSL:1 MANE Select	c.868-6801_868-6800insATAT		intron	N/A	ENSP00000418532.1	P35503-1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0498 AC: 1506 AN: 30268

American (AMR) AF: 0.00361 AC: 148 AN: 41012

Ashkenazi Jewish (ASJ) AF: 0.000760 AC: 18 AN: 23678

East Asian (EAS) AF: 0.000332 AC: 12 AN: 36156

South Asian (SAS) AF: 0.00182 AC: 140 AN: 76888

European-Finnish (FIN) AF: 0.00135 AC: 60 AN: 44550

Middle Eastern (MID) AF: 0.00268 AC: 10 AN: 3730

European-Non Finnish (NFE) AF: 0.00123 AC: 1250 AN: 1020100

Other (OTH) AF: 0.00407 AC: 224 AN: 54972

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0504 AC: 2080 AN: 41284

American (AMR) AF: 0.00415 AC: 63 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4790

European-Finnish (FIN) AF: 0.000485 AC: 5 AN: 10312

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000738 AC: 50 AN: 67712

Other (OTH) AF: 0.0119 AC: 25 AN: 2098

Alfa AF: 0.00 Hom.: 268

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; drug response

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	1	not provided (4)
-	1	-	not specified (1)
1	-	-	UGT1A1-related disorder (1)
-	1	-	UGT1A9-related disorder (1)
-	-	-	Irinotecan response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3064744; hg19: chr2-234668879;