chr2-233760233-C-CAT

Variant names:

• chr2-233760233-C-CAT
• rs3064744
• NM_007120.3:c.868-6787_868-6786dupTA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_007120.3(UGT1A4):​c.868-6787_868-6786dupTA 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 NM_007120.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity; drug response; other criteria provided, conflicting classifications P:17 U:3 B:3 O:4
• Conservation: PhyloP100: 0.148
• Publications: 53 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

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.868-6787_868-6786dupTA		intron	N/A	NP_009051.1	P22310-1
	UGT1A5	NM_019078.2	MANE Select	c.868-6787_868-6786dupTA		intron	N/A	NP_061951.1	Q5DSZ9
	UGT1A3	NM_019093.4	MANE Select	c.868-6787_868-6786dupTA		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_868-6800insAT		intron	N/A	ENSP00000362508.4	P22310-1
	UGT1A5	ENST00000373414.4	TSL:1 MANE Select	c.868-6801_868-6800insAT		intron	N/A	ENSP00000362513.3	P35504-1
	UGT1A3	ENST00000482026.6	TSL:1 MANE Select	c.868-6801_868-6800insAT		intron	N/A	ENSP00000418532.1	P35503-1

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

African (AFR) AF: 0.345 AC: 10580 AN: 30672

American (AMR) AF: 0.283 AC: 11419 AN: 40400

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 8031 AN: 23674

East Asian (EAS) AF: 0.120 AC: 4237 AN: 35196

South Asian (SAS) AF: 0.358 AC: 27540 AN: 76888

European-Finnish (FIN) AF: 0.343 AC: 15215 AN: 44366

Middle Eastern (MID) AF: 0.314 AC: 1164 AN: 3708

European-Non Finnish (NFE) AF: 0.299 AC: 301178 AN: 1006186

Other (OTH) AF: 0.301 AC: 16373 AN: 54348

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

African (AFR) AF: 0.398 AC: 16421 AN: 41270

American (AMR) AF: 0.320 AC: 4861 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1318 AN: 3460

East Asian (EAS) AF: 0.126 AC: 651 AN: 5156

South Asian (SAS) AF: 0.408 AC: 1952 AN: 4788

European-Finnish (FIN) AF: 0.417 AC: 4295 AN: 10306

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21655 AN: 67684

Other (OTH) AF: 0.319 AC: 668 AN: 2096

Alfa AF: 0.168 Hom.: 268

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; drug response; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	1	1	Gilbert syndrome (8)
5	-	1	not provided (7)
3	-	-	Crigler-Najjar syndrome, type II (3)
-	1	1	not specified (2)
1	-	-	Crigler-Najjar syndrome (1)
1	-	-	Crigler-Najjar syndrome type 1 (1)
-	1	-	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 (1)
1	-	-	Lucey-Driscoll syndrome (1)
1	-	-	UGT1A1-related disorder (1)
-	-	-	BILIRUBIN, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS 1 (1)
-	-	-	Irinotecan response (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV59387575; COSMIC: COSV59387575;