NM_019093.4:c.477A>G

Variant names:

• chr2-233729603-A-G
• rs7574296
• NM_019093.4:c.477A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_019093.4(UGT1A3):​c.477A>G​(p.Ala159Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,688 control chromosomes in the GnomAD database, including 180,593 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 0.54 (23579 hom., cov: 31)
  • Exomes 𝑓: 0.46 (157014 hom.)
• Consequence: UGT1A3 NM_019093.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.64
• Publications: 31 publications found

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:12529):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP7: Synonymous conserved (PhyloP=-6.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019093.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A3	NM_019093.4	MANE Select	c.477A>G	p.Ala159Ala	synonymous	Exon 1 of 5	NP_061966.1	Q5DT01
	UGT1A4	NM_007120.3	MANE Select	c.867+9916A>G		intron	N/A	NP_009051.1	P22310-1
	UGT1A5	NM_019078.2	MANE Select	c.867+15745A>G		intron	N/A	NP_061951.1	Q5DSZ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A3	ENST00000482026.6	TSL:1 MANE Select	c.477A>G	p.Ala159Ala	synonymous	Exon 1 of 5	ENSP00000418532.1	P35503-1
	UGT1A4	ENST00000373409.8	TSL:1 MANE Select	c.867+9916A>G		intron	N/A	ENSP00000362508.4	P22310-1
	UGT1A5	ENST00000373414.4	TSL:1 MANE Select	c.867+15745A>G		intron	N/A	ENSP00000362513.3	P35504-1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81593 AN: 151852 Hom.: 23563 Cov.: 31

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.506

GnomAD2 exomes AF: 0.485 AC: 121982 AN: 251272 AF XY: 0.487

Gnomad AFR exome AF: 0.766

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.457 AC: 668243 AN: 1461718 Hom.: 157014 Cov.: 114 AF XY: 0.461 AC XY: 335312 AN XY: 727164

African (AFR) AF: 0.766 AC: 25633 AN: 33472

American (AMR) AF: 0.468 AC: 20927 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 13994 AN: 26130

East Asian (EAS) AF: 0.287 AC: 11412 AN: 39700

South Asian (SAS) AF: 0.599 AC: 51689 AN: 86252

European-Finnish (FIN) AF: 0.472 AC: 25187 AN: 53418

Middle Eastern (MID) AF: 0.536 AC: 3088 AN: 5764

European-Non Finnish (NFE) AF: 0.439 AC: 487669 AN: 1111882

Other (OTH) AF: 0.474 AC: 28644 AN: 60382

GnomAD4 genome AF: 0.537 AC: 81650 AN: 151970 Hom.: 23579 Cov.: 31 AF XY: 0.535 AC XY: 39775 AN XY: 74280

African (AFR) AF: 0.759 AC: 31458 AN: 41428

American (AMR) AF: 0.479 AC: 7313 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1855 AN: 3466

East Asian (EAS) AF: 0.327 AC: 1692 AN: 5174

South Asian (SAS) AF: 0.600 AC: 2874 AN: 4792

European-Finnish (FIN) AF: 0.486 AC: 5140 AN: 10566

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29703 AN: 67962

Other (OTH) AF: 0.507 AC: 1069 AN: 2110

Alfa AF: 0.490 Hom.: 11483

Bravo AF: 0.543

Asia WGS AF: 0.471 AC: 1637 AN: 3478

EpiCase AF: 0.455

EpiControl AF: 0.454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.29
PhyloP100		-6.6
Mutation Taster		=100/0	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: rs7574296; hg19: chr2-234638249; COSMIC: COSV59384679;