rs587776761

Positions:

• chr2-233767045-CTACATTAATGCTTC-CA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_007120.3(UGT1A4):​c.880_893delinsA​(p.Tyr294MetfsTer69) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UGT1A4 NM_007120.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.03

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]

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]

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]

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]

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-233767046-TACATTAATGCTTC-A is Pathogenic according to our data. Variant chr2-233767046-TACATTAATGCTTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 12266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A1	NM_000463.3	c.877_890delinsA	p.Tyr293MetfsTer69	frameshift_variant	2/5	ENST00000305208.10
UGT1A6	NM_001072.4	c.874_887delinsA	p.Tyr292MetfsTer69	frameshift_variant	2/5	ENST00000305139.11
UGT1A4	NM_007120.3	c.880_893delinsA	p.Tyr294MetfsTer69	frameshift_variant	2/5	ENST00000373409.8
UGT1A10	NM_019075.4	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	ENST00000344644.10
UGT1A8	NM_019076.5	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	ENST00000373450.5
UGT1A7	NM_019077.3	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	ENST00000373426.4
UGT1A5	NM_019078.2	c.880_893delinsA	p.Tyr294MetfsTer69	frameshift_variant	2/5	ENST00000373414.4
UGT1A3	NM_019093.4	c.880_893delinsA	p.Tyr294MetfsTer69	frameshift_variant	2/5	ENST00000482026.6
UGT1A9	NM_021027.3	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A6	ENST00000305139.11	c.874_887delinsA	p.Tyr292MetfsTer69	frameshift_variant	2/5	1	NM_001072.4	P1
UGT1A1	ENST00000305208.10	c.877_890delinsA	p.Tyr293MetfsTer69	frameshift_variant	2/5	1	NM_000463.3	P1
UGT1A10	ENST00000344644.10	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	1	NM_021027.3	P1
UGT1A4	ENST00000373409.8	c.880_893delinsA	p.Tyr294MetfsTer69	frameshift_variant	2/5	1	NM_007120.3	P1
UGT1A5	ENST00000373414.4	c.880_893delinsA	p.Tyr294MetfsTer69	frameshift_variant	2/5	1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.868_881delinsA	p.Tyr290MetfsTer69	frameshift_variant	2/5	1	NM_019076.5	P1
UGT1A3	ENST00000482026.6	c.880_893delinsA	p.Tyr294MetfsTer69	frameshift_variant	2/5	1	NM_019093.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 19, 2022	For these reasons, this variant has been classified as Pathogenic. This variant is also known as "13-nt deletion in exon 2 (877T > A 878–890del)," "878_890delinsA," or "879_890delinsA". This premature translational stop signal has been observed in individual(s) with Crigler-Najjar syndrome (PMID: 1634606, 11855932, 18058623). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr293Metfs*69) in the UGT1A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UGT1A1 are known to be pathogenic (PMID: 23290513). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2016	- -

Crigler-Najjar syndrome type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1992	- -
Pathogenic, no assertion criteria provided	research	Neonatal Research Center, Shiraz University of Medical Science	Feb 04, 2021	The c.874_887delinsA variant is a null variant (frameshift) in the UGT1A1 gene. Loss-of-function mutation is a known mechanism of CNS-1. This variant is absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. The c.874_887delinsA variant was well-established in vitro functional studies supportive of a damaging effect on the UGT1A1 gene product (Francoual et al.). This variant is assumed de novo, but without confirmation of paternity and maternity. We identified an Indel mutation (c.874_887delinsA; p.Tyr292fs) in the second exon of the UGT1A1 gene identified in a 3 months old girl. The patient is the offspring of unrelated parents. There was no similar disease in the three-generation pedigree. Unconjugated serum bilirubin concentration increased and reached 28.1 mg/dL and didn’t decrease significantly by phototherapy and phenobarbital administration. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776761; hg19: chr2-234675692;