2-233760912-C-T

Position:

• chr2-233760912-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000463.3(UGT1A1):​c.625C>T​(p.Arg209Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,614,070 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (1 hom.)
• Consequence: UGT1A1 NM_000463.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.822

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 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 2-233760912-C-T is Pathogenic according to our data. Variant chr2-233760912-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233760912-C-T is described in Lovd as [Pathogenic]. Variant chr2-233760912-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A1	NM_000463.3	c.625C>T	p.Arg209Trp	missense_variant	1/5	ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4	c.862-6122C>T		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A4	NM_007120.3	c.868-6122C>T		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A10	NM_019075.4	c.856-6122C>T		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-6122C>T		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-6122C>T		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.868-6122C>T		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-6122C>T		intron_variant		ENST00000482026.6	NP_061966.1
UGT1A9	NM_021027.3	c.856-6122C>T		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A1	ENST00000305208.10	c.625C>T	p.Arg209Trp	missense_variant	1/5	1	NM_000463.3	ENSP00000304845	P1
UGT1A6	ENST00000305139.11	c.862-6122C>T		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-6122C>T		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.856-6122C>T		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A4	ENST00000373409.8	c.868-6122C>T		intron_variant		1	NM_007120.3	ENSP00000362508	P1
UGT1A5	ENST00000373414.4	c.868-6122C>T		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.856-6122C>T		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-6122C>T		intron_variant		1	NM_019076.5	ENSP00000362549	P1
UGT1A3	ENST00000482026.6	c.868-6122C>T		intron_variant		1	NM_019093.4	ENSP00000418532	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251492 Hom.: 1 AF XY: 0.0000368 AC XY: 5 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461884 Hom.: 1 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000502 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crigler-Najjar syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2016

- -

UGT1A1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2023

The UGT1A1 c.625C>T variant is predicted to result in the amino acid substitution p.Arg209Trp. This variant was reported in the homozygous state in two related individuals with Crigler-Najjar syndrome 2 (Bosma et al. 1993. PubMed ID: 8514037; Sneitz et al. 2010. PubMed ID: 19830808), and in the homozygous state in another individual with Crigler-Najjar syndrome type II (Yamamoto et al. 1998. PubMed ID: 9621515). This variant was also reported, along with a second plausible causative variant, in patients with Crigler-Najjar syndrome types I or II (Bai et al. 2021. PubMed ID: 34007799; Abuduxikuer et al. 2018. PubMed ID: 30544479). Lastly, this variant was described in another individual who presented with Crigler-Najjar syndrome; however, a second plausible causative variant was not identified (Perretti et al. 2007. PubMed ID: 18058623). The c.625C>T variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/2-234669558-C-T). This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Dec 17, 2022

- -

Crigler-Najjar syndrome, type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Diagnostics Department, Viafet Genomics Laboratory

Aug 23, 2021

Viafet Genomics Laboratory has identified this variant in a homozygous state in a patient affected with Crigler-Najjar syndrome. In addition, as part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in another patient who is not affected with this condition. This variant has been identified in a homozygous state in patients affected with Crigler-Najjar syndrome (PMIDs: 8514037, 9621515 and 19830808). In addition, functional study performed by Sneitz et al., 2010 has shown a significant decrease in Bilirubin glucuronidation activity compared to the wildtype (PMID: 19830808). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.94		Gain of catalytic residue at L207 (P = 0.0036);Gain of catalytic residue at L207 (P = 0.0036);
MVP		0.90
MPC		0.56
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.74
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72551343; hg19: chr2-234669558;