rs34946978

Variant names:

• chr2-233768226-C-T
• rs34946978
• NM_007120.3:c.1094C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-233768226-C-T
• chr2-233768226-C-A
• chr2-233768226-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3 PM1 PP3 PP5 BP4

The NM_007120.3(UGT1A4):​c.1094C>T​(p.Pro365Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,614,202 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). ClinVar reports functional evidence for this variant: "SCV000521290: Published functional studies demonstrate a damaging effect with 35.6% enzyme activity compared to wild type (PMID:15304120, 21726413)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (7 hom.)
• Consequence: UGT1A4 NM_007120.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:11 U:5 O:1
• Conservation: PhyloP100: 7.62
• Publications: 71 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000521290: Published functional studies demonstrate a damaging effect with 35.6% enzyme activity compared to wild type (PMID: 15304120, 21726413); SCV000884824: "In vitro functional analyses of this variant demonstrated a significant reduction in the UGT1A1 enzyme activity (Takeuchi 2004)." PMID: 15304120; SCV005905280: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15304120).; SCV004103709: Functional studies using COS7 cells showed that the p.Pro364Leu substitution reduced UGT1A1 activity by ~ 64% (Takeuchi et al. 2004. PubMed ID: 15304120; Mimura et al. 2011. PubMed ID: 21726413).; SCV007097034: "COS-7 cells transfected with this variant had a 64.4% reduction in UGT1A1 activity compared to wild type cells;"
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_007120.3
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 2-233768226-C-T is Pathogenic according to our data. Variant chr2-233768226-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity|other. ClinVar VariationId is 212543.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019219369). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A4	NM_007120.3	MANE Select	c.1094C>T	p.Pro365Leu	missense	Exon 4 of 5	NP_009051.1	P22310-1
	UGT1A5	NM_019078.2	MANE Select	c.1094C>T	p.Pro365Leu	missense	Exon 4 of 5	NP_061951.1	Q5DSZ9
	UGT1A3	NM_019093.4	MANE Select	c.1094C>T	p.Pro365Leu	missense	Exon 4 of 5	NP_061966.1	Q5DT01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A4	ENST00000373409.8	TSL:1 MANE Select	c.1094C>T	p.Pro365Leu	missense	Exon 4 of 5	ENSP00000362508.4	P22310-1
	UGT1A5	ENST00000373414.4	TSL:1 MANE Select	c.1094C>T	p.Pro365Leu	missense	Exon 4 of 5	ENSP00000362513.3	P35504-1
	UGT1A3	ENST00000482026.6	TSL:1 MANE Select	c.1094C>T	p.Pro365Leu	missense	Exon 4 of 5	ENSP00000418532.1	P35503-1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00124 AC: 309 AN: 249048 AF XY: 0.00108

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000420 AC: 614 AN: 1461890 Hom.: 7 Cov.: 36 AF XY: 0.000421 AC XY: 306 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00907 AC: 360 AN: 39700

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1112012

Other (OTH) AF: 0.00108 AC: 65 AN: 60394

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74476

African (AFR) AF: 0.000217 AC: 9 AN: 41570

American (AMR) AF: 0.00176 AC: 27 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000643 Hom.: 1

Bravo AF: 0.00126

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Gilbert syndrome (4)
3	1	-	not provided (5)
1	1	-	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 (2)
1	-	-	Crigler-Najjar syndrome type 1 (1)
-	1	-	Crigler-Najjar syndrome type 1;C0017551:Gilbert syndrome;C0270210:Lucey-Driscoll syndrome;C2931132:Crigler-Najjar syndrome, type II (1)
1	-	-	Crigler-Najjar syndrome, type II (1)
1	-	-	Hyperbilirubinemia (1)
-	1	-	not specified (1)
1	-	-	UGT1A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.95
MPC		0.21
ClinPred		0.89	D
GERP RS		5.9
Varity_R		0.67
gMVP		0.54
Mutation Taster		=3/97	disease causing

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: rs34946978; hg19: chr2-234676872; COSMIC: COSV59380860; COSMIC: COSV59380860;