rs1042597

chr2-233618225-C-Achr2-233618225-C-Gchr2-233618225-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019076.5(UGT1A8):c.518C>A(p.Ala173Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A173G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: UGT1A8 NM_019076.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.179

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26266813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A8	NM_019076.5	c.518C>A	p.Ala173Asp	missense_variant	1/5	ENST00000373450.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A8	ENST00000373450.5	c.518C>A	p.Ala173Asp	missense_variant	1/5	1	NM_019076.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	8.1
Dann	Benign	0.78
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.11
Sift	Uncertain	0.020	D
Sift4G	Benign	0.12	T
Polyphen		0.25	B
Vest4		0.30
MutPred		0.46		Gain of phosphorylation at Y176 (P = 0.0961);
MVP		0.28
ClinPred		0.17	T
GERP RS		-0.18
Varity_R		0.11
gMVP		0.37

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

Other links and lift over

dbSNP: rs1042597; hg19: chr2-234526871;