2-233618153-C-A

Variant summary

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

The NM_019076.5(UGT1A8):​c.446C>A​(p.Pro149His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,874 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 (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

UGT1A8
NM_019076.5 missense

Scores

8
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
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]

Genome browser will be placed here

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, 0.943

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
UGT1A8NM_019076.5 linkuse as main transcriptc.446C>A p.Pro149His missense_variant 1/5 ENST00000373450.5 NP_061949.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
UGT1A8ENST00000373450.5 linkuse as main transcriptc.446C>A p.Pro149His missense_variant 1/51 NM_019076.5 ENSP00000362549 P1Q9HAW9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251406
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461874
Hom.:
0
Cov.:
32
AF XY:
0.0000220
AC XY:
16
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000130
Hom.:
0
Bravo
AF:
0.0000189
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 GeneticsApr 30, 2024The c.446C>A (p.P149H) alteration is located in exon 1 (coding exon 1) of the UGT1A8 gene. This alteration results from a C to A substitution at nucleotide position 446, causing the proline (P) at amino acid position 149 to be replaced by a histidine (H). 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
Pathogenic
0.74
BayesDel_addAF
Uncertain
0.085
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.057
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Pathogenic
3.8
H
MutationTaster
Benign
1.0
D
PROVEAN
Pathogenic
-8.4
D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.81
MutPred
0.77
Loss of stability (P = 0.2547);
MVP
0.85
ClinPred
0.99
D
GERP RS
4.0
Varity_R
0.77
gMVP
0.36

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: rs891600440; hg19: chr2-234526799; COSMIC: COSV100990662; API