rs3755321

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.10 ( 911 hom., cov: 32)

Exomes 𝑓: 0.098 ( 7869 hom. )

Consequence

UGT1A5
NM_019078.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.77

Variant links:

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]

UGT1A5 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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UGT1A5	NM_019078.2 linkuse as main transcript	c.188T>C	p.Leu63Pro	missense_variant	1/5	ENST00000373414.4
UGT1A6	NM_001072.4 linkuse as main transcript	c.861+19314T>C		intron_variant		ENST00000305139.11
UGT1A10	NM_019075.4 linkuse as main transcript	c.856-53855T>C		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5 linkuse as main transcript	c.856-53855T>C		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3 linkuse as main transcript	c.855+30387T>C		intron_variant		ENST00000373426.4
UGT1A9	NM_021027.3 linkuse as main transcript	c.855+40390T>C		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A5	ENST00000373414.4 linkuse as main transcript	c.188T>C	p.Leu63Pro	missense_variant	1/5	1	NM_019078.2	P1	P35504-1
UGT1A6	ENST00000305139.11 linkuse as main transcript	c.861+19314T>C		intron_variant		1	NM_001072.4	P1	P19224-1
UGT1A10	ENST00000344644.10 linkuse as main transcript	c.856-53855T>C		intron_variant		1	NM_019075.4	P1	Q9HAW8-1
UGT1A9	ENST00000354728.5 linkuse as main transcript	c.855+40390T>C		intron_variant		1	NM_021027.3	P1	O60656-1
UGT1A7	ENST00000373426.4 linkuse as main transcript	c.855+30387T>C		intron_variant		1	NM_019077.3	P1	Q9HAW7-1
UGT1A8	ENST00000373450.5 linkuse as main transcript	c.856-53855T>C		intron_variant		1	NM_019076.5	P1	Q9HAW9-1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15465

AN:

152180

Hom.:

907

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.119

AC:

29793

AN:

251414

Hom.:

2108

AF XY:

0.122

AC XY:

16533

AN XY:

135886

show subpopulations

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 SAS exome

AF:

0.199

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.:

AF XY:

0.101

AC XY:

73335

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.126

Gnomad4 ASJ exome

AF:

0.103

Gnomad4 EAS exome

AF:

0.167

Gnomad4 SAS exome

AF:

0.197

Gnomad4 FIN exome

AF:

0.0720

Gnomad4 NFE exome

AF:

0.0866

Gnomad4 OTH exome

AF:

0.106

GnomAD4 genome

AF:

0.102

AC:

15484

AN:

152298

Hom.:

911

Cov.:

AF XY:

0.103

AC XY:

7637

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.112

Gnomad4 ASJ

AF:

0.102

Gnomad4 EAS

AF:

0.204

Gnomad4 SAS

AF:

0.199

Gnomad4 FIN

AF:

0.0604

Gnomad4 NFE

AF:

0.0903

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.0968

Hom.:

1882

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

Cadd

Benign

2.2

Dann

Benign

0.61

DEOGEN2

Benign

0.040

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0074

LIST_S2

Benign

0.059

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-3.2

MutationTaster

Benign

0.0000014

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

PROVEAN

Benign

8.4

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.048

MPC

0.26

ClinPred

0.0083

GERP RS

4.0

Varity_R

0.11

gMVP

0.27

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over