rs4148323

chr2-233760498-G-Achr2-233760498-G-C

• Frequency:
  • Genomes: 𝑓 0.011 (89 hom., cov: 33)
  • Exomes 𝑓: 0.022 (276 hom.)
• Consequence: UGT1A1 NM_000463.3 missense
• Clinical Significance: Conflicting interpretations of pathogenicity; drug response criteria provided, conflicting interpretations P:9 U:2 B:3 O:4
• Conservation: PhyloP100: 3.90

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016674995).
• BA1: GnomAd highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A1	NM_000463.3	c.211G>A	p.Gly71Arg	missense_variant	1/5	ENST00000305208.10
UGT1A6	NM_001072.4	c.862-6536G>A		intron_variant		ENST00000305139.11
UGT1A4	NM_007120.3	c.868-6536G>A		intron_variant		ENST00000373409.8
UGT1A10	NM_019075.4	c.856-6536G>A		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-6536G>A		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.856-6536G>A		intron_variant		ENST00000373426.4
UGT1A5	NM_019078.2	c.868-6536G>A		intron_variant		ENST00000373414.4
UGT1A3	NM_019093.4	c.868-6536G>A		intron_variant		ENST00000482026.6
UGT1A9	NM_021027.3	c.856-6536G>A		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A1	ENST00000305208.10	c.211G>A	p.Gly71Arg	missense_variant	1/5	1	NM_000463.3	P1
UGT1A6	ENST00000305139.11	c.862-6536G>A		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-6536G>A		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.856-6536G>A		intron_variant		1	NM_021027.3	P1
UGT1A4	ENST00000373409.8	c.868-6536G>A		intron_variant		1	NM_007120.3	P1
UGT1A5	ENST00000373414.4	c.868-6536G>A		intron_variant		1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.856-6536G>A		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-6536G>A		intron_variant		1	NM_019076.5	P1
UGT1A3	ENST00000482026.6	c.868-6536G>A		intron_variant		1	NM_019093.4	P1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1720 AN: 152230 Hom.: 89 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.0223 AC: 5619 AN: 251430 Hom.: 276 AF XY: 0.0215 AC XY: 2923 AN XY: 135890

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.154

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0461

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00901 AC: 13165 AN: 1461888 Hom.: 721 AF XY: 0.00931 AC XY: 6769 AN XY: 727246

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.0428

Gnomad4 NFE exome AF: 0.000782

Gnomad4 OTH exome AF: 0.0107

Alfa AF: 0.00667 Hom.: 150

Bravo AF: 0.0100

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0207 AC: 2507

Asia WGS AF: 0.0630 AC: 220 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting interpretations of pathogenicity; drug response

Submissions summary: Pathogenic:9Uncertain:2Benign:3Other:4

Revision: criteria provided, conflicting interpretations

LINK:

Submissions by phenotype

not provided Pathogenic:5Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 71 of the UGT1A1 protein (p.Gly71Arg). This variant is present in population databases (rs4148323, gnomAD 15%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with UGT1A1-related hyperbilirubinemia. Homozygous individuals for this variant present with Gilbert syndrome (PMID: 19397531, 20975617, 21272068, 21342357, 25200497, 11061796). In some cases this variant has been reported to occur on the same chromosome (in cis) with p.Tyr486Asp, forming a haplotype. Homozygous individuals for this haplotype present with Crigler-Najjar syndrome type II (PMID: 9630669, 21319362, 15304120). This variant is also known as UGT1A1*6. ClinVar contains an entry for this variant (Variation ID: 12280). 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) performed at Invitae indicates that this missense variant is not expected to disrupt UGT1A1 protein function. Experimental studies have shown that this missense change affects UGT1A1 function (PMID: 9630669, 19830808). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2022	Published functional studies demonstrate a damaging effect with reduced UGTA1A protein activity, especially when the variant is in the homozygous state or in the presence of additional UGT1A1 pathogenic variants (Yamamoto K et al., 1998; Sneitz N et al., 2010; Gagn JF et al., 2002; Tagawa K et al., 2022); Also known as UGT1A1*6; This variant is associated with the following publications: (PMID: 31207142, 29607327, 20975617, 25967674, 20504240, 23014115, 25200497, 24615032, 23388413, 25262004, 19243019, 23875061, 26716871, 21342357, 20528217, 19325249, 20924216, 24749086, 22046580, 21319362, 21092520, 7715297, 34007799, 16255851, 29115431, 19397531, 17850628, 21272068, 28100328, 31122244, 29179591, 30298137, 9621515, 30669781, 34074250, 31737051, 32287101, 32762156, 24448639, 11316168, 24519753, 29534743, 12502904, 27895797, 24308720, 35131284, 28585035, 26830078, 28520360, 24033692, 27220761, 18004206, 19390945, 26857783, 26604633, 11061796, 10472535, 9929972, 26417955, 24492252, 19830808, 12181437, 9784835, 16610035, 25087612, 35930428, 9630669, 8280139, 21297505, 27323053, 29137095, 15304120, 10412811) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2022	The UGT1A1 c.211G>A; p.Gly71Arg variant, also known as the *6 allele, is associated with an increased incidence of neonatal hyperbilirubinemia (Akaba 1999, Maruo 2000), and when homozygous, causes Gilbert syndrome (Takeuchi 2004). Functional analyses of the variant protein show decreased maximum enzyme activity (Udomuksorn 2007). This variant is found predominantly in the East Asian population with an overall frequency of 15.3% (3053/19950 alleles, including 250 homozygotes) in the Genome Aggregation Database. One study also suggests that neonates with the UGT1A1*6 allele experiencing a greater than 5% weight loss in the first 72 hours after birth have a higher incidence of hyperbilirubinemia (Sato 2013). Furthermore, when homozygous or in combination with other UGT1A1 promoter variants (e.g., greater than 6 TA repeats), this variant may predict an increased risk of irinotecan-related neutropenia (Barbarino 2014, Han 2014). There is currently insufficient evidence regarding the clinical impact of the *6 allele in patients treated with atazanavir (Gammal 2016, Park 2010). Based on available information, this variant is classified as a mildly pathogenic variant. References: Akaba K et al. Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese. J Hum Genet. 1999;44(1):22-5. PMID: 9929972 Barbarino JM et al. PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenet Genomics. Pharmacogenet Genomics. 2014 Mar;24(3):177-83. PMID: 24492252 Gammal RS et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016 Apr;99(4):363-9. PMID: 26417955 Han FF et al. Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patientsCancer Chemother Pharmacol. 2014 Apr;73(4):779-88. PMID: 24519753 Maruo Y et al. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate- glucuronosyltransferase gene. Pediatrics. 2000 Nov;106(5):E59. PMID: 11061796 Park WB et al. Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency. Clin Infect Dis. 2010 Jul 1;51(1):101-6. PMID: 20504240 Sato H et al. Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G>A (G71R) mutation becomes a risk factor under inadequate feeding. J Hum Genet. 2013 Jan;58(1):7-10. PMID: 23014115 Takeuchi K et al. Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects. J Gastroenterol Hepatol. 2004 Sep;19(9):1023-8. PMID: 15304120 Udomuksorn W et al. Influence of mutations associated with Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates. Pharmacogenet Genomics. 2007 Dec. PMID: 18004206 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Jan 20, 2021	This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Gilbert syndrome Pathogenic:2Benign:1Other:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	The c.211G>A (p.Gly71Arg) missense variant in the UGT1A1 gene is a known common variant associated with Gilbert Syndrome and hyperbilirubinemia in individuals of East Asian descent. Numerous case-control studies have demonstrated this variant is significantly prevalent in affected individuals relative to unaffected controls (Fu and Liu, 2005; Lin et al., 2009; Zhou et al., 2009; Prachukthum et al., 2009; Gao et al., 2010; Long et al., 2011a; Long et al., 2011b; Chen et al., 2014). Multiple in vitro studies have shown that this variant leads to reduced enzymatic activity, and this variant is associated with elevated serum bilirubin in infants (Yamamoto et al., 1998; Sneitz et al., 2010; Chou et al., 2011). The allele frequency is high in the population databases for individuals of East Asian descent, which is expected given the high prevalence of the disease (1000 Genomes = 13.8% [EAS]; ExAC = 15.24% [EAS]). Hence, a yet unknown genetic modifier that is specific to the East Asian population may contribute to the high disease prevalence. Finally, a reputable clinical diagnostic laboratory has reported this variant as Likely Pathogenic (University of Chicago). Together, this collective evidence supports the classification of the c.211G>A (p.Gly71Arg) as a Likely Pathogenic variant for Gilbert Syndrome. -
Affects, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
other, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 25, 2016	- reduced function allele
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, no assertion criteria provided	case-control	Difficult and Complicated Liver Diseases and Artificial Liver Center, Beijing You An Hospital, Capital Medical University	May 01, 2019	- -

not specified Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, PreventionGenetics	-	- -

Lucey-Driscoll syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

Crigler-Najjar syndrome, type II Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Irinotecan response Other:1

drug response, criteria provided, single submitter

curation

Medical Genetics Summaries

Apr 04, 2018

UGT1A1*6 appears to be an important predictor of severe toxicity to irinotecan therapy in Asian populations. In Japan, a reduced dose of irinotecan is recommended for individuals with UGT1A1 *6/*6, *6/*28, and *28/*28 genotypes. Poor metabolizer

Bilirubin, serum level of, quantitative trait locus 1 Other:1

association, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.61

T

BayesDel_noAF

Benign

-0.50

Cadd

Uncertain

24

Dann

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.077

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.34

N

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

T

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.60

P;P;P;P;P;P;P;P;P;P;P;P;P

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.14

Sift

Benign

0.040

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.98

D;.

Vest4

0.067

MutPred

0.57

Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);

MPC

0.34

ClinPred

0.032

T

GERP RS

5.1

Varity_R

0.17

gMVP

0.40

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: rs4148323; hg19: chr2-234669144; COSMIC: COSV59383881; COSMIC: COSV59383881;