2-233772999-G-C

Variant names:

• chr2-233772999-G-C
• rs8330
• ENST00000450233.1:n.*841G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000450233.1(UGT1A4):​n.*841G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 238,554 control chromosomes in the GnomAD database, including 68,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.73 (41000 hom., cov: 32)
  • Exomes 𝑓: 0.79 (27191 hom.)
• Consequence: UGT1A4 ENST00000450233.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.320
• Publications: 64 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]

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]

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):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 2-233772999-G-C is Benign according to our data. Variant chr2-233772999-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335086.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A4	NM_007120.3	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000482026.6	NP_061966.1
UGT1A1	NM_000463.3	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_019078.2	ENSP00000362513.3
UGT1A3	ENST00000482026.6	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_019093.4	ENSP00000418532.1
UGT1A1	ENST00000305208.10	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_000463.3	ENSP00000304845.5
UGT1A6	ENST00000305139.11	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.*440G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110649 AN: 151936 Hom.: 40966 Cov.: 32

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.770

Gnomad OTH AF: 0.713

GnomAD4 exome AF: 0.790 AC: 68324 AN: 86500 Hom.: 27191 Cov.: 2 AF XY: 0.793 AC XY: 35956 AN XY: 45334

African (AFR) AF: 0.595 AC: 1432 AN: 2406

American (AMR) AF: 0.741 AC: 3177 AN: 4288

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 1408 AN: 2078

East Asian (EAS) AF: 0.884 AC: 4173 AN: 4718

South Asian (SAS) AF: 0.824 AC: 9785 AN: 11876

European-Finnish (FIN) AF: 0.867 AC: 3275 AN: 3778

Middle Eastern (MID) AF: 0.821 AC: 230 AN: 280

European-Non Finnish (NFE) AF: 0.786 AC: 41426 AN: 52722

Other (OTH) AF: 0.785 AC: 3418 AN: 4354

GnomAD4 genome AF: 0.728 AC: 110735 AN: 152054 Hom.: 41000 Cov.: 32 AF XY: 0.737 AC XY: 54749 AN XY: 74334

African (AFR) AF: 0.588 AC: 24345 AN: 41428

American (AMR) AF: 0.744 AC: 11359 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2372 AN: 3472

East Asian (EAS) AF: 0.882 AC: 4564 AN: 5176

South Asian (SAS) AF: 0.819 AC: 3947 AN: 4818

European-Finnish (FIN) AF: 0.883 AC: 9341 AN: 10580

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.770 AC: 52387 AN: 67996

Other (OTH) AF: 0.712 AC: 1502 AN: 2110

Alfa AF: 0.760 Hom.: 21795

Bravo AF: 0.709

Asia WGS AF: 0.830 AC: 2887 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Lucey-Driscoll syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Crigler-Najjar syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Gilbert syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.3
DANN	Benign	0.51
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8330; hg19: chr2-234681645;