rs72551353

Positions:

chr2-233768259-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_007120.3(UGT1A4):c.1127C>T(p.Ser376Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,010 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

UGT1A4
NM_007120.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.73

Variant links:

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]

UGT1A4 links:

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]

UGT1A5 links:

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]

UGT1A3 links:

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]

UGT1A1 links:

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]

UGT1A6 links:

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]

UGT1A10 links:

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]

UGT1A8 links:

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]

UGT1A7 links:

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]

UGT1A9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 2-233768259-C-T is Pathogenic according to our data. Variant chr2-233768259-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233768259-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
UGT1A4	NM_007120.3 linkuse as main transcript	c.1127C>T	p.Ser376Phe	missense_variant	4/5	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2 linkuse as main transcript	c.1127C>T	p.Ser376Phe	missense_variant	4/5	ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4 linkuse as main transcript	c.1127C>T	p.Ser376Phe	missense_variant	4/5	ENST00000482026.6	NP_061966.1
UGT1A1	NM_000463.3 linkuse as main transcript	c.1124C>T	p.Ser375Phe	missense_variant	4/5	ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4 linkuse as main transcript	c.1121C>T	p.Ser374Phe	missense_variant	4/5	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8 linkuse as main transcript	c.1127C>T	p.Ser376Phe	missense_variant	4/5	1	NM_007120.3	ENSP00000362508	P1	P22310-1
UGT1A5	ENST00000373414.4 linkuse as main transcript	c.1127C>T	p.Ser376Phe	missense_variant	4/5	1	NM_019078.2	ENSP00000362513	P1	P35504-1
UGT1A3	ENST00000482026.6 linkuse as main transcript	c.1127C>T	p.Ser376Phe	missense_variant	4/5	1	NM_019093.4	ENSP00000418532	P1	P35503-1
UGT1A1	ENST00000305208.10 linkuse as main transcript	c.1124C>T	p.Ser375Phe	missense_variant	4/5	1	NM_000463.3	ENSP00000304845	P1	P22309-1
UGT1A6	ENST00000305139.11 linkuse as main transcript	c.1121C>T	p.Ser374Phe	missense_variant	4/5	1	NM_001072.4	ENSP00000303174	P1	P19224-1
UGT1A10	ENST00000344644.10 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	1	NM_019075.4	ENSP00000343838	P1	Q9HAW8-1
UGT1A9	ENST00000354728.5 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	1	NM_021027.3	ENSP00000346768	P1	O60656-1
UGT1A7	ENST00000373426.4 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	1	NM_019077.3	ENSP00000362525	P1	Q9HAW7-1
UGT1A8	ENST00000373450.5 linkuse as main transcript	c.1115C>T	p.Ser372Phe	missense_variant	4/5	1	NM_019076.5	ENSP00000362549	P1	Q9HAW9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Crigler-Najjar syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 18, 2023

Variant summary: UGT1A1 c.1124C>T (p.Ser375Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249056 control chromosomes (gnomAD). c.1124C>T has been reported in the literature as a biallelic genotype in individuals affected with Crigler-Najjar syndrome (e.g. Bosma_1992, Erps_1994, Servedio_2005). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Erps_1994). The most pronounced variant effect results in undetectable enzyme activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 1634050, 7906695, 15712364). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 375 of the UGT1A1 protein (p.Ser375Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Crigler-Najjar syndrome type I (PMID: 1634050, 7906695). ClinVar contains an entry for this variant (Variation ID: 12267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UGT1A1 protein function. Experimental studies have shown that this missense change affects UGT1A1 function (PMID: 7906695). For these reasons, this variant has been classified as Pathogenic. -

Crigler-Najjar syndrome type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;.;D;D;.;D;.;T;T;T;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.031

MutationAssessor

Pathogenic

3.5

.;.;.;M;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.1

D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;T;D;D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;D;.;D;.;D;D;D;D;.

Vest4

0.90

MutPred

0.87

.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0743);Loss of disorder (P = 0.0743);Loss of disorder (P = 0.0743);.;.;

MVP

0.95

MPC

0.22, 0.35, 0.55, 0.54, 0.72, 0.21, 0.21, 0.58

ClinPred

1.0

GERP RS

5.9

Varity_R

0.91

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over