chr2-233713179-T-C

Variant names:

• chr2-233713179-T-C
• rs3755321
• NM_019078.2:c.188T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019078.2(UGT1A5):​c.188T>C​(p.Leu63Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0981 in 1,614,156 control chromosomes in the GnomAD database, including 8,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (911 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7869 hom.)
• Consequence: UGT1A5 NM_019078.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 20 publications found

Genes affected

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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002122581).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019078.2. 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
	UGT1A5	NM_019078.2	MANE Select	c.188T>C	p.Leu63Pro	missense	Exon 1 of 5	NP_061951.1
	UGT1A6	NM_001072.4	MANE Select	c.861+19314T>C		intron	N/A	NP_001063.2
	UGT1A10	NM_019075.4	MANE Select	c.856-53855T>C		intron	N/A	NP_061948.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A5	ENST00000373414.4	TSL:1 MANE Select	c.188T>C	p.Leu63Pro	missense	Exon 1 of 5	ENSP00000362513.3
	UGT1A6	ENST00000305139.11	TSL:1 MANE Select	c.861+19314T>C		intron	N/A	ENSP00000303174.6
	UGT1A10	ENST00000344644.10	TSL:1 MANE Select	c.856-53855T>C		intron	N/A	ENSP00000343838.5

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15465 AN: 152180 Hom.: 907 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0604

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.119 AC: 29793 AN: 251414 AF XY: 0.122

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.0662

Gnomad NFE exome AF: 0.0921

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0977 AC: 142810 AN: 1461858 Hom.: 7869 Cov.: 34 AF XY: 0.101 AC XY: 73335 AN XY: 727224

African (AFR) AF: 0.103 AC: 3449 AN: 33480

American (AMR) AF: 0.126 AC: 5619 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2695 AN: 26136

East Asian (EAS) AF: 0.167 AC: 6649 AN: 39698

South Asian (SAS) AF: 0.197 AC: 17017 AN: 86258

European-Finnish (FIN) AF: 0.0720 AC: 3847 AN: 53418

Middle Eastern (MID) AF: 0.140 AC: 810 AN: 5768

European-Non Finnish (NFE) AF: 0.0866 AC: 96319 AN: 1111984

Other (OTH) AF: 0.106 AC: 6405 AN: 60392

GnomAD4 genome AF: 0.102 AC: 15484 AN: 152298 Hom.: 911 Cov.: 32 AF XY: 0.103 AC XY: 7637 AN XY: 74464

African (AFR) AF: 0.104 AC: 4328 AN: 41570

American (AMR) AF: 0.112 AC: 1707 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3472

East Asian (EAS) AF: 0.204 AC: 1060 AN: 5184

South Asian (SAS) AF: 0.199 AC: 961 AN: 4824

European-Finnish (FIN) AF: 0.0604 AC: 641 AN: 10616

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0903 AC: 6140 AN: 68008

Other (OTH) AF: 0.117 AC: 247 AN: 2116

Alfa AF: 0.0977 Hom.: 2937

Bravo AF: 0.103

TwinsUK AF: 0.0841 AC: 312

ALSPAC AF: 0.0877 AC: 338

ESP6500AA AF: 0.103 AC: 452

ESP6500EA AF: 0.0863 AC: 742

ExAC AF: 0.121 AC: 14682

Asia WGS AF: 0.199 AC: 690 AN: 3478

EpiCase AF: 0.0946

EpiControl AF: 0.0943

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.2
DANN	Benign	0.61
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.059	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-3.2	N
PhyloP100		2.8
PROVEAN	Benign	8.4	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.048
MPC		0.26
ClinPred		0.0083	T
GERP RS		4.0
PromoterAI		-0.013	Neutral
Varity_R		0.11
gMVP		0.27
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3755321; hg19: chr2-234621825; COSMIC: COSV59399434; COSMIC: COSV59399434;