2-233672363-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_021027.3(UGT1A9):ā€‹c.429T>Gā€‹(p.Asp143Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

UGT1A9
NM_021027.3 missense

Scores

2
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.689
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_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
UGT1A9NM_021027.3 linkuse as main transcriptc.429T>G p.Asp143Glu missense_variant 1/5 ENST00000354728.5 NP_066307.1
UGT1A10NM_019075.4 linkuse as main transcriptc.855+34986T>G intron_variant ENST00000344644.10 NP_061948.1
UGT1A8NM_019076.5 linkuse as main transcriptc.855+53801T>G 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.429T>G p.Asp143Glu missense_variant 1/51 NM_021027.3 ENSP00000346768 P1O60656-1
UGT1A10ENST00000344644.10 linkuse as main transcriptc.855+34986T>G intron_variant 1 NM_019075.4 ENSP00000343838 P1Q9HAW8-1
UGT1A8ENST00000373450.5 linkuse as main transcriptc.855+53801T>G intron_variant 1 NM_019076.5 ENSP00000362549 P1Q9HAW9-1
UGT1A10ENST00000373445.1 linkuse as main transcriptc.855+34986T>G intron_variant 1 ENSP00000362544 Q9HAW8-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251172
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000217
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:
0.00000274
AC:
4
AN:
1461848
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
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
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 05, 2024The c.429T>G (p.D143E) alteration is located in exon 1 (coding exon 1) of the UGT1A9 gene. This alteration results from a T to G substitution at nucleotide position 429, causing the aspartic acid (D) at amino acid position 143 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.0055
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.014
T
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.40
T
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
1.0
D;D;D;N
PROVEAN
Uncertain
-3.6
D
REVEL
Uncertain
0.56
Sift
Benign
0.045
D
Sift4G
Benign
0.074
T
Polyphen
0.97
D
Vest4
0.81
MutPred
0.88
Gain of disorder (P = 0.1607);
MVP
0.73
MPC
0.29
ClinPred
0.71
D
GERP RS
0.95
Varity_R
0.27
gMVP
0.60

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: rs751596599; hg19: chr2-234581009; API