2-233693267-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001072.4(UGT1A6):c.263A>G(p.Lys88Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

UGT1A6
NM_001072.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.400

Variant links:

Genes affected

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:

UGT1A (HGNC:12529):

UGT1A links:

ENSG00000224814 (HGNC:):

ENSG00000224814 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048870593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A6	NM_001072.4 link	c.263A>G	p.Lys88Arg	missense_variant	Exon 1 of 5	ENST00000305139.11	NP_001063.2	P19224-1Q5DSZ8
UGT1A10	NM_019075.4 link	c.855+55890A>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1	Q9HAW8-1Q5DT02
UGT1A8	NM_019076.5 link	c.856-73767A>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3	Q9HAW9-1Q5DSZ6
UGT1A7	NM_019077.3 link	c.855+10475A>G		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2	Q9HAW7-1Q5DSZ7
UGT1A9	NM_021027.3 link	c.855+20478A>G		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1	O60656-1Q5DSZ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UGT1A6	ENST00000305139.11 link	c.263A>G	p.Lys88Arg	missense_variant	Exon 1 of 5	1	NM_001072.4	ENSP00000303174.6	P19224-1
UGT1A10	ENST00000344644.10 link	c.855+55890A>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5	Q9HAW8-1
UGT1A9	ENST00000354728.5 link	c.855+20478A>G		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4	O60656-1
UGT1A7	ENST00000373426.4 link	c.855+10475A>G		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3	Q9HAW7-1
UGT1A8	ENST00000373450.5 link	c.856-73767A>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4	Q9HAW9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251238

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000403

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263A>G (p.K88R) alteration is located in exon 1 (coding exon 1) of the UGT1A6 gene. This alteration results from a A to G substitution at nucleotide position 263, causing the lysine (K) at amino acid position 88 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 09, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.4

DANN

Benign

0.85

DEOGEN2

Benign

0.022

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.31

T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.45

.;N

PROVEAN

Benign

-0.85

N;N

REVEL

Benign

0.037

Sift

Benign

0.25

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0

.;B

Vest4

0.035

MutPred

0.45

Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);

MVP

0.39

MPC

0.081

ClinPred

0.014

GERP RS

-0.33

Varity_R

0.051

gMVP

0.12

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