NM_000463.3:c.211G>A

Variant names:

• chr2-233760498-G-A
• rs4148323
• NM_000463.3:c.211G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_000463.3(UGT1A1):​c.211G>A​(p.Gly71Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00922 in 1,614,236 control chromosomes in the GnomAD database, including 811 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (90 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (721 hom.)
• Consequence: UGT1A1 NM_000463.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; drug response criteria provided, conflicting classifications P:16 U:3 B:4 O:4
• Conservation: PhyloP100: 3.90
• Publications: 489 publications found

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]

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]

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: Benign. The variant received -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.2468 (below the threshold of 3.09). Trascript score misZ: 0.17712 (below the threshold of 3.09). GenCC associations: The gene is linked to Crigler-Najjar syndrome type 1, Crigler-Najjar syndrome type 2, Gilbert syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016674995).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000463.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A1	NM_000463.3	MANE Select	c.211G>A	p.Gly71Arg	missense	Exon 1 of 5	NP_000454.1
	UGT1A4	NM_007120.3	MANE Select	c.868-6536G>A		intron	N/A	NP_009051.1
	UGT1A5	NM_019078.2	MANE Select	c.868-6536G>A		intron	N/A	NP_061951.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A1	ENST00000305208.10	TSL:1 MANE Select	c.211G>A	p.Gly71Arg	missense	Exon 1 of 5	ENSP00000304845.5
	UGT1A1	ENST00000360418.4	TSL:1	c.211G>A	p.Gly71Arg	missense	Exon 1 of 5	ENSP00000353593.3
	UGT1A4	ENST00000373409.8	TSL:1 MANE Select	c.868-6536G>A		intron	N/A	ENSP00000362508.4

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

GnomAD2 exomes AF: 0.0223 AC: 5619 AN: 251430 AF XY: 0.0215

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 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 Cov.: 34 AF XY: 0.00931 AC XY: 6769 AN XY: 727246

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.0220 AC: 985 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26136

East Asian (EAS) AF: 0.166 AC: 6583 AN: 39700

South Asian (SAS) AF: 0.0192 AC: 1652 AN: 86258

European-Finnish (FIN) AF: 0.0428 AC: 2287 AN: 53414

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000782 AC: 870 AN: 1112012

Other (OTH) AF: 0.0107 AC: 648 AN: 60396

GnomAD4 genome AF: 0.0113 AC: 1721 AN: 152348 Hom.: 90 Cov.: 33 AF XY: 0.0151 AC XY: 1127 AN XY: 74498

African (AFR) AF: 0.000818 AC: 34 AN: 41584

American (AMR) AF: 0.0116 AC: 178 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.154 AC: 801 AN: 5186

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4828

European-Finnish (FIN) AF: 0.0472 AC: 501 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68038

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00630 Hom.: 242

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; drug response

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	1	-	not provided (7)
4	-	2	Gilbert syndrome (8)
-	1	2	not specified (3)
2	-	-	Lucey-Driscoll syndrome (2)
1	-	-	Crigler-Najjar syndrome type 1 (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 (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	-	-	UGT1A1-related disorder (1)
-	-	-	BILIRUBIN, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS 1 (1)
-	-	-	Irinotecan response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.040	D
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.067
MutPred		0.57		Gain of solvent accessibility (P = 0.0055)
MPC		0.34
ClinPred		0.032	T
GERP RS		5.1
PromoterAI		-0.020	Neutral
Varity_R		0.17
gMVP		0.40
Mutation Taster		=83/17	polymorphism (auto)

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