2-233768234-C-T

Variant names:

• chr2-233768234-C-T
• rs55750087
• NM_007120.3:c.1102C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007120.3(UGT1A4):​c.1102C>T​(p.Arg368Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: UGT1A4 NM_007120.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.72

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A4	NM_007120.3	c.1102C>T	p.Arg368Cys	missense_variant	Exon 4 of 5	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.1102C>T	p.Arg368Cys	missense_variant	Exon 4 of 5	ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.1102C>T	p.Arg368Cys	missense_variant	Exon 4 of 5	ENST00000482026.6	NP_061966.1
UGT1A1	NM_000463.3	c.1099C>T	p.Arg367Cys	missense_variant	Exon 4 of 5	ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4	c.1096C>T	p.Arg366Cys	missense_variant	Exon 4 of 5	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8	c.1102C>T	p.Arg368Cys	missense_variant	Exon 4 of 5	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.1102C>T	p.Arg368Cys	missense_variant	Exon 4 of 5	1	NM_019078.2	ENSP00000362513.3
UGT1A3	ENST00000482026.6	c.1102C>T	p.Arg368Cys	missense_variant	Exon 4 of 5	1	NM_019093.4	ENSP00000418532.1
UGT1A1	ENST00000305208.10	c.1099C>T	p.Arg367Cys	missense_variant	Exon 4 of 5	1	NM_000463.3	ENSP00000304845.5
UGT1A6	ENST00000305139.11	c.1096C>T	p.Arg366Cys	missense_variant	Exon 4 of 5	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.1090C>T	p.Arg364Cys	missense_variant	Exon 4 of 5	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249050 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134814

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1461892 Hom.: 0 Cov.: 36 AF XY: 0.0000523 AC XY: 38 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74340

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000104 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 367 of the UGT1A1 protein (p.Arg367Cys). This variant is present in population databases (rs55750087, gnomAD 0.006%). This missense change has been observed in individual(s) with Crigler-Najjar syndrome type II (PMID: 23099197). ClinVar contains an entry for this variant (Variation ID: 288098). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UGT1A1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 12, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 Uncertain:1

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

UGT1A1-related disorder Uncertain:1

Apr 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The UGT1A1 c.1099C>T variant is predicted to result in the amino acid substitution p.Arg367Cys. This variant has been reported in the compound heterozygous state in an individual with neonatal unconjugated hyperbilirubinemia (Minucci et al. 2013. PubMed ID: 23099197). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;.;D;D;.;D;.;T;T;T;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.8	.;.;.;H;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;.;D;.;D;D;D;D;.
Vest4		0.73
MVP		0.89
MPC		0.23, 0.38, 0.61, 0.60, 0.80, 0.23, 0.22, 0.64
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.79
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs55750087; hg19: chr2-234676880; COSMIC: COSV105180094; COSMIC: COSV105180094;