rs17868336

Positions:

• chr2-233729360-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_019093.4(UGT1A3):​c.234A>G​(p.Thr78Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,614,118 control chromosomes in the GnomAD database, including 1,450 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (72 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1378 hom.)
• Consequence: UGT1A3 NM_019093.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.151

Genes affected

UGT1A3 (HGNC:12535): (UDP glucuronosyltransferase family 1 member A3) 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. Substrates of this enzyme include estrone, 2-hydroxyestrone, and metabolites of benzo alpha-pyrene. [provided by RefSeq, Jul 2008]

UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) 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. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [provided by RefSeq, Jul 2008]

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:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0253 (3852/152314) while in subpopulation NFE AF= 0.0411 (2795/68022). AF 95% confidence interval is 0.0398. There are 72 homozygotes in gnomad4. There are 1694 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 72 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A3	NM_019093.4	c.234A>G	p.Thr78Thr	synonymous_variant	1/5	ENST00000482026.6	NP_061966.1
UGT1A4	NM_007120.3	c.867+9673A>G		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.867+15502A>G		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+35495A>G		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-37674A>G		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-37674A>G		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-37674A>G		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.856-37674A>G		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A3	ENST00000482026.6	c.234A>G	p.Thr78Thr	synonymous_variant	1/5	1	NM_019093.4	ENSP00000418532.1
UGT1A4	ENST00000373409.8	c.867+9673A>G		intron_variant		1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.867+15502A>G		intron_variant		1	NM_019078.2	ENSP00000362513.3
UGT1A6	ENST00000305139.11	c.861+35495A>G		intron_variant		1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-37674A>G		intron_variant		1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.856-37674A>G		intron_variant		1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.856-37674A>G		intron_variant		1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-37674A>G		intron_variant		1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3857 AN: 152196 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0232 AC: 5825 AN: 251350 Hom.: 118 AF XY: 0.0222 AC XY: 3020 AN XY: 135844

Gnomad AFR exome AF: 0.00874

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0390 AC: 56942 AN: 1461804 Hom.: 1378 Cov.: 99 AF XY: 0.0375 AC XY: 27268 AN XY: 727198

Gnomad4 AFR exome AF: 0.00690

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.0472

Gnomad4 OTH exome AF: 0.0341

GnomAD4 genome AF: 0.0253 AC: 3852 AN: 152314 Hom.: 72 Cov.: 33 AF XY: 0.0227 AC XY: 1694 AN XY: 74484

Gnomad4 AFR AF: 0.00921

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0411

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0335 Hom.: 41

Bravo AF: 0.0264

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0376

EpiControl AF: 0.0402

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.72
DANN	Benign	0.51

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: rs17868336; hg19: chr2-234638006;