chr2-233767812-T-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0130

Publications

9 publications found
Variant links:
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]

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ACMG classification

Classification was made for transcript

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
UGT1A4NM_007120.3 linkc.1000-37T>C intron_variant Intron 2 of 4 ENST00000373409.8 NP_009051.1 P22310-1
UGT1A5NM_019078.2 linkc.1000-37T>C intron_variant Intron 2 of 4 ENST00000373414.4 NP_061951.1 P35504-1Q5DSZ9
UGT1A3NM_019093.4 linkc.1000-37T>C intron_variant Intron 2 of 4 ENST00000482026.6 NP_061966.1 P35503-1Q5DT01
UGT1A1NM_000463.3 linkc.997-37T>C intron_variant Intron 2 of 4 ENST00000305208.10 NP_000454.1 P22309-1Q5DT03
UGT1A6NM_001072.4 linkc.994-37T>C intron_variant Intron 2 of 4 ENST00000305139.11 NP_001063.2 P19224-1Q5DSZ8
UGT1A10NM_019075.4 linkc.988-37T>C intron_variant Intron 2 of 4 ENST00000344644.10 NP_061948.1 Q9HAW8-1Q5DT02
UGT1A8NM_019076.5 linkc.988-37T>C intron_variant Intron 2 of 4 ENST00000373450.5 NP_061949.3 Q9HAW9-1Q5DSZ6
UGT1A7NM_019077.3 linkc.988-37T>C intron_variant Intron 2 of 4 ENST00000373426.4 NP_061950.2 Q9HAW7-1Q5DSZ7
UGT1A9NM_021027.3 linkc.988-37T>C intron_variant Intron 2 of 4 ENST00000354728.5 NP_066307.1 O60656-1Q5DSZ5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UGT1A4ENST00000373409.8 linkc.1000-37T>C intron_variant Intron 2 of 4 1 NM_007120.3 ENSP00000362508.4 P22310-1
UGT1A5ENST00000373414.4 linkc.1000-37T>C intron_variant Intron 2 of 4 1 NM_019078.2 ENSP00000362513.3 P35504-1
UGT1A3ENST00000482026.6 linkc.1000-37T>C intron_variant Intron 2 of 4 1 NM_019093.4 ENSP00000418532.1 P35503-1
UGT1A1ENST00000305208.10 linkc.997-37T>C intron_variant Intron 2 of 4 1 NM_000463.3 ENSP00000304845.5 P22309-1
UGT1A6ENST00000305139.11 linkc.994-37T>C intron_variant Intron 2 of 4 1 NM_001072.4 ENSP00000303174.6 P19224-1
UGT1A10ENST00000344644.10 linkc.988-37T>C intron_variant Intron 2 of 4 1 NM_019075.4 ENSP00000343838.5 Q9HAW8-1
UGT1A9ENST00000354728.5 linkc.988-37T>C intron_variant Intron 2 of 4 1 NM_021027.3 ENSP00000346768.4 O60656-1
UGT1A7ENST00000373426.4 linkc.988-37T>C intron_variant Intron 2 of 4 1 NM_019077.3 ENSP00000362525.3 Q9HAW7-1
UGT1A8ENST00000373450.5 linkc.988-37T>C intron_variant Intron 2 of 4 1 NM_019076.5 ENSP00000362549.4 Q9HAW9-1

Frequencies

GnomAD3 genomes
AF:
0.0385
AC:
5859
AN:
152166
Hom.:
159
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
3046
6093
9139
12186
15232
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
1214
2428
3642
4856
6070
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0386
AC:
5882
AN:
152284
Hom.:
161
Cov.:
32
AF XY:
0.0389
AC XY:
2898
AN XY:
74470
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
287
575
862
1150
1437
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
70
140
210
280
350
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
LINK: link

Submissions by phenotype

not provided Benign:1
Jul 10, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

Publications

Other links and lift over

dbSNP: rs12471326; hg19: chr2-234676458; COSMIC: COSV59384614; API