chr2-233760794-ATTC-A
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000463.3(UGT1A1):c.513_515delCTT(p.Phe171del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000958 in 1,461,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
UGT1A1
NM_000463.3 disruptive_inframe_deletion
NM_000463.3 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.04
Publications
1 publications found
Genes affected
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]
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]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 13 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000463.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000463.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 2-233760794-ATTC-A is Pathogenic according to our data. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760794-ATTC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 12271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| UGT1A1 | NM_000463.3 | c.513_515delCTT | p.Phe171del | disruptive_inframe_deletion | Exon 1 of 5 | ENST00000305208.10 | NP_000454.1 | |
| UGT1A4 | NM_007120.3 | c.868-6234_868-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000373409.8 | NP_009051.1 | ||
| UGT1A5 | NM_019078.2 | c.868-6234_868-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000373414.4 | NP_061951.1 | ||
| UGT1A3 | NM_019093.4 | c.868-6234_868-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000482026.6 | NP_061966.1 | ||
| UGT1A6 | NM_001072.4 | c.862-6234_862-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000305139.11 | NP_001063.2 | ||
| UGT1A10 | NM_019075.4 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000344644.10 | NP_061948.1 | ||
| UGT1A8 | NM_019076.5 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000373450.5 | NP_061949.3 | ||
| UGT1A7 | NM_019077.3 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000373426.4 | NP_061950.2 | ||
| UGT1A9 | NM_021027.3 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | ENST00000354728.5 | NP_066307.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| UGT1A1 | ENST00000305208.10 | c.513_515delCTT | p.Phe171del | disruptive_inframe_deletion | Exon 1 of 5 | 1 | NM_000463.3 | ENSP00000304845.5 | ||
| UGT1A4 | ENST00000373409.8 | c.868-6234_868-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_007120.3 | ENSP00000362508.4 | |||
| UGT1A5 | ENST00000373414.4 | c.868-6234_868-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_019078.2 | ENSP00000362513.3 | |||
| UGT1A3 | ENST00000482026.6 | c.868-6234_868-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_019093.4 | ENSP00000418532.1 | |||
| UGT1A6 | ENST00000305139.11 | c.862-6234_862-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_001072.4 | ENSP00000303174.6 | |||
| UGT1A10 | ENST00000344644.10 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_019075.4 | ENSP00000343838.5 | |||
| UGT1A9 | ENST00000354728.5 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_021027.3 | ENSP00000346768.4 | |||
| UGT1A7 | ENST00000373426.4 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_019077.3 | ENSP00000362525.3 | |||
| UGT1A8 | ENST00000373450.5 | c.856-6234_856-6232delCTT | intron_variant | Intron 1 of 4 | 1 | NM_019076.5 | ENSP00000362549.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD2 exomes AF: 0.0000119 AC: 3AN: 251264 AF XY: 0.0000147 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
251264
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
AF:
Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461312Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 726864 show subpopulations
GnomAD4 exome
AF:
AC:
14
AN:
1461312
Hom.:
AF XY:
AC XY:
8
AN XY:
726864
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33450
American (AMR)
AF:
AC:
0
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26108
East Asian (EAS)
AF:
AC:
0
AN:
39690
South Asian (SAS)
AF:
AC:
0
AN:
86250
European-Finnish (FIN)
AF:
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
14
AN:
1111556
Other (OTH)
AF:
AC:
0
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
2
3
5
6
8
0.00
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0.40
0.60
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
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8
10
<30
30-35
35-40
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50-55
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Jun 14, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects UGT1A1 function (PMID: 8226884). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 12271). This variant is also known as c.508_510delTTC and p.Phe170del. This variant has been observed in individual(s) with Crigler-Najjar syndrome type I and Crigler-Najjar syndrome type II (PMID: 8226884, 9039987, 23099197, 25319636). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs769799339, gnomAD 0.003%). This variant, c.513_515del, results in the deletion of 1 amino acid(s) of the UGT1A1 protein (p.Phe171del), but otherwise preserves the integrity of the reading frame. -
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 Pathogenic:1
Jan 10, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Crigler-Najjar syndrome type 1 Pathogenic:1
Mar 01, 2005
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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