2-233713464-C-G

Variant names:

• chr2-233713464-C-G
• rs12475068
• NM_019078.2:c.473C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019078.2(UGT1A5):​c.473C>G​(p.Ala158Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0981 in 1,613,912 control chromosomes in the GnomAD database, including 8,805 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (907 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7898 hom.)
• Consequence: UGT1A5 NM_019078.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.09
• Publications: 22 publications found

Genes affected

UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) 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. [provided by RefSeq, Jul 2008]

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]

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]

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]

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]

UGT1A (HGNC:12529):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023413599).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A5	NM_019078.2	c.473C>G	p.Ala158Gly	missense_variant	Exon 1 of 5	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+19599C>G		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-53570C>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-53570C>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+30672C>G		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+40675C>G		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A5	ENST00000373414.4	c.473C>G	p.Ala158Gly	missense_variant	Exon 1 of 5	1	NM_019078.2	ENSP00000362513.3
UGT1A6	ENST00000305139.11	c.861+19599C>G		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-53570C>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+40675C>G		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.855+30672C>G		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-53570C>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15441 AN: 152050 Hom.: 903 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0599

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.119 AC: 29806 AN: 251422 AF XY: 0.122

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.0922

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0977 AC: 142832 AN: 1461744 Hom.: 7898 Cov.: 34 AF XY: 0.101 AC XY: 73340 AN XY: 727156

African (AFR) AF: 0.103 AC: 3446 AN: 33472

American (AMR) AF: 0.126 AC: 5618 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2695 AN: 26136

East Asian (EAS) AF: 0.168 AC: 6651 AN: 39700

South Asian (SAS) AF: 0.197 AC: 17007 AN: 86202

European-Finnish (FIN) AF: 0.0720 AC: 3847 AN: 53418

Middle Eastern (MID) AF: 0.140 AC: 809 AN: 5766

European-Non Finnish (NFE) AF: 0.0867 AC: 96353 AN: 1111946

Other (OTH) AF: 0.106 AC: 6406 AN: 60386

GnomAD4 genome AF: 0.102 AC: 15460 AN: 152168 Hom.: 907 Cov.: 32 AF XY: 0.102 AC XY: 7624 AN XY: 74394

African (AFR) AF: 0.104 AC: 4325 AN: 41520

American (AMR) AF: 0.112 AC: 1706 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3466

East Asian (EAS) AF: 0.205 AC: 1061 AN: 5168

South Asian (SAS) AF: 0.198 AC: 950 AN: 4806

European-Finnish (FIN) AF: 0.0599 AC: 635 AN: 10596

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6136 AN: 68006

Other (OTH) AF: 0.117 AC: 247 AN: 2110

Alfa AF: 0.0626 Hom.: 98

Bravo AF: 0.103

TwinsUK AF: 0.0852 AC: 316

ALSPAC AF: 0.0895 AC: 345

ESP6500AA AF: 0.102 AC: 451

ESP6500EA AF: 0.0863 AC: 742

ExAC AF: 0.121 AC: 14684

Asia WGS AF: 0.200 AC: 692 AN: 3476

EpiCase AF: 0.0946

EpiControl AF: 0.0943

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.0
DANN	Benign	0.55
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.050	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-3.1	N
PhyloP100		4.1
PROVEAN	Benign	5.0	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.16
ClinPred		0.0097	T
GERP RS		4.9
Varity_R		0.069
gMVP		0.37
Mutation Taster		=60/40	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12475068; hg19: chr2-234622110; COSMIC: COSV59382165; COSMIC: COSV59382165;