2-233671942-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_021027.3(UGT1A9):​c.8G>A​(p.Cys3Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,610,580 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

UGT1A9
NM_021027.3 missense

Scores

18

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.404
Variant links:
Genes affected
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0058830082).
BP6
Variant 2-233671942-G-A is Benign according to our data. Variant chr2-233671942-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3358191.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
UGT1A9NM_021027.3 linkuse as main transcriptc.8G>A p.Cys3Tyr missense_variant 1/5 ENST00000354728.5 NP_066307.1
UGT1A10NM_019075.4 linkuse as main transcriptc.855+34565G>A intron_variant ENST00000344644.10 NP_061948.1
UGT1A8NM_019076.5 linkuse as main transcriptc.855+53380G>A intron_variant ENST00000373450.5 NP_061949.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
UGT1A9ENST00000354728.5 linkuse as main transcriptc.8G>A p.Cys3Tyr missense_variant 1/51 NM_021027.3 ENSP00000346768 P1O60656-1
UGT1A10ENST00000344644.10 linkuse as main transcriptc.855+34565G>A intron_variant 1 NM_019075.4 ENSP00000343838 P1Q9HAW8-1
UGT1A8ENST00000373450.5 linkuse as main transcriptc.855+53380G>A intron_variant 1 NM_019076.5 ENSP00000362549 P1Q9HAW9-1
UGT1A10ENST00000373445.1 linkuse as main transcriptc.855+34565G>A intron_variant 1 ENSP00000362544 Q9HAW8-2

Frequencies

GnomAD3 genomes
AF:
0.000874
AC:
133
AN:
152216
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00137
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:
0.00126
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000870
AC:
215
AN:
247208
Hom.:
0
AF XY:
0.000832
AC XY:
111
AN XY:
133404
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.00189
Gnomad ASJ exome
AF:
0.000103
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000942
Gnomad NFE exome
AF:
0.00118
Gnomad OTH exome
AF:
0.00183
GnomAD4 exome
AF:
0.00111
AC:
1615
AN:
1458246
Hom.:
1
Cov.:
33
AF XY:
0.00103
AC XY:
747
AN XY:
725202
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.00193
Gnomad4 ASJ exome
AF:
0.0000387
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.00130
Gnomad4 OTH exome
AF:
0.00124
GnomAD4 genome
AF:
0.000873
AC:
133
AN:
152334
Hom.:
0
Cov.:
32
AF XY:
0.000806
AC XY:
60
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000553
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00126
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00128
Hom.:
1
Bravo
AF:
0.00106
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00163
AC:
14
ExAC
AF:
0.000923
AC:
112

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

UGT1A9-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 01, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
0.85
DANN
Benign
0.34
DEOGEN2
Benign
0.18
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.030
N
LIST_S2
Benign
0.27
T
M_CAP
Benign
0.0077
T
MetaRNN
Benign
0.0059
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
N;N;N;N
PROVEAN
Benign
-0.14
N
REVEL
Benign
0.034
Sift
Benign
0.64
T
Sift4G
Benign
0.28
T
Polyphen
0.0040
B
Vest4
0.21
MVP
0.37
MPC
0.077
ClinPred
0.0012
T
GERP RS
2.6
Varity_R
0.035
gMVP
0.30

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.

Other links and lift over

dbSNP: rs145084767; hg19: chr2-234580588; API