2-233767812-T-C

Variant names:

• chr2-233767812-T-C
• rs12471326
• NM_007120.3:c.1000-37T>C

Variant summary

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

The NM_007120.3(UGT1A4):​c.1000-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,614,140 control chromosomes in the GnomAD database, including 974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (161 hom., cov: 32)
  • Exomes 𝑓: 0.029 (813 hom.)
• Consequence: UGT1A4 NM_007120.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0130
• Publications: 9 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=-0.81).
• BP6: Variant 2-233767812-T-C is Benign according to our data. Variant chr2-233767812-T-C is described in ClinVar as [Benign]. Clinvar id is 1261103.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.067 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A4	NM_007120.3	c.1000-37T>C		intron_variant	Intron 2 of 4	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.1000-37T>C		intron_variant	Intron 2 of 4	ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.1000-37T>C		intron_variant	Intron 2 of 4	ENST00000482026.6	NP_061966.1
UGT1A1	NM_000463.3	c.997-37T>C		intron_variant	Intron 2 of 4	ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4	c.994-37T>C		intron_variant	Intron 2 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.988-37T>C		intron_variant	Intron 2 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.988-37T>C		intron_variant	Intron 2 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.988-37T>C		intron_variant	Intron 2 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.988-37T>C		intron_variant	Intron 2 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8	c.1000-37T>C		intron_variant	Intron 2 of 4	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.1000-37T>C		intron_variant	Intron 2 of 4	1	NM_019078.2	ENSP00000362513.3
UGT1A3	ENST00000482026.6	c.1000-37T>C		intron_variant	Intron 2 of 4	1	NM_019093.4	ENSP00000418532.1
UGT1A1	ENST00000305208.10	c.997-37T>C		intron_variant	Intron 2 of 4	1	NM_000463.3	ENSP00000304845.5
UGT1A6	ENST00000305139.11	c.994-37T>C		intron_variant	Intron 2 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.988-37T>C		intron_variant	Intron 2 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.988-37T>C		intron_variant	Intron 2 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.988-37T>C		intron_variant	Intron 2 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.988-37T>C		intron_variant	Intron 2 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5859 AN: 152166 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0420

GnomAD2 exomes AF: 0.0376 AC: 9370 AN: 248950 AF XY: 0.0351

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.00386

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0411

GnomAD4 exome AF: 0.0292 AC: 42748 AN: 1461856 Hom.: 813 Cov.: 36 AF XY: 0.0288 AC XY: 20956 AN XY: 727234

African (AFR) AF: 0.0466 AC: 1560 AN: 33480

American (AMR) AF: 0.0961 AC: 4298 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 1282 AN: 26136

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39694

South Asian (SAS) AF: 0.0188 AC: 1619 AN: 86256

European-Finnish (FIN) AF: 0.0263 AC: 1402 AN: 53396

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5768

European-Non Finnish (NFE) AF: 0.0275 AC: 30560 AN: 1112010

Other (OTH) AF: 0.0299 AC: 1803 AN: 60396

GnomAD4 genome AF: 0.0386 AC: 5882 AN: 152284 Hom.: 161 Cov.: 32 AF XY: 0.0389 AC XY: 2898 AN XY: 74470

African (AFR) AF: 0.0533 AC: 2216 AN: 41540

American (AMR) AF: 0.0705 AC: 1079 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3470

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5174

South Asian (SAS) AF: 0.0155 AC: 75 AN: 4826

European-Finnish (FIN) AF: 0.0263 AC: 279 AN: 10624

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0284 AC: 1929 AN: 68032

Other (OTH) AF: 0.0421 AC: 89 AN: 2116

Alfa AF: 0.0342 Hom.: 152

Bravo AF: 0.0429

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.71
PhyloP100		0.013
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: rs12471326; hg19: chr2-234676458; COSMIC: COSV59384614;