2-233729157-T-C

Variant names:

• chr2-233729157-T-C
• rs3821242
• NM_019093.4:c.31T>C

Variant summary

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

The NM_019093.4(UGT1A3):​c.31T>C​(p.Trp11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,613,154 control chromosomes in the GnomAD database, including 172,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.50 (19815 hom., cov: 33)
  • Exomes 𝑓: 0.45 (152762 hom.)
• Consequence: UGT1A3 NM_019093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 51 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.550415E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A3	NM_019093.4	c.31T>C	p.Trp11Arg	missense_variant	Exon 1 of 5	ENST00000482026.6	NP_061966.1
UGT1A4	NM_007120.3	c.867+9470T>C		intron_variant	Intron 1 of 4	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.867+15299T>C		intron_variant	Intron 1 of 4	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+35292T>C		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-37877T>C		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-37877T>C		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-37877T>C		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.856-37877T>C		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A3	ENST00000482026.6	c.31T>C	p.Trp11Arg	missense_variant	Exon 1 of 5	1	NM_019093.4	ENSP00000418532.1
UGT1A4	ENST00000373409.8	c.867+9470T>C		intron_variant	Intron 1 of 4	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.867+15299T>C		intron_variant	Intron 1 of 4	1	NM_019078.2	ENSP00000362513.3
UGT1A6	ENST00000305139.11	c.861+35292T>C		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-37877T>C		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.856-37877T>C		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.856-37877T>C		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-37877T>C		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76193 AN: 152008 Hom.: 19810 Cov.: 33

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.481

GnomAD2 exomes AF: 0.475 AC: 119227 AN: 250966 AF XY: 0.479

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.453 AC: 661365 AN: 1461028 Hom.: 152762 Cov.: 92 AF XY: 0.457 AC XY: 332228 AN XY: 726808

African (AFR) AF: 0.642 AC: 21488 AN: 33450

American (AMR) AF: 0.461 AC: 20602 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 13574 AN: 26132

East Asian (EAS) AF: 0.287 AC: 11409 AN: 39700

South Asian (SAS) AF: 0.599 AC: 51620 AN: 86212

European-Finnish (FIN) AF: 0.471 AC: 25182 AN: 53414

Middle Eastern (MID) AF: 0.517 AC: 2754 AN: 5330

European-Non Finnish (NFE) AF: 0.438 AC: 486772 AN: 1111754

Other (OTH) AF: 0.464 AC: 27964 AN: 60322

GnomAD4 genome AF: 0.501 AC: 76235 AN: 152126 Hom.: 19815 Cov.: 33 AF XY: 0.500 AC XY: 37207 AN XY: 74392

African (AFR) AF: 0.637 AC: 26417 AN: 41482

American (AMR) AF: 0.465 AC: 7111 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1810 AN: 3466

East Asian (EAS) AF: 0.327 AC: 1695 AN: 5180

South Asian (SAS) AF: 0.599 AC: 2886 AN: 4818

European-Finnish (FIN) AF: 0.486 AC: 5147 AN: 10592

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29608 AN: 67972

Other (OTH) AF: 0.482 AC: 1018 AN: 2114

Alfa AF: 0.445 Hom.: 10354

Bravo AF: 0.502

TwinsUK AF: 0.430 AC: 1594

ALSPAC AF: 0.446 AC: 1718

ESP6500AA AF: 0.628 AC: 2766

ESP6500EA AF: 0.444 AC: 3816

ExAC AF: 0.479 AC: 58143

Asia WGS AF: 0.465 AC: 1616 AN: 3478

EpiCase AF: 0.454

EpiControl AF: 0.452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.051
DANN	Benign	0.29
DEOGEN2	Benign	0.071	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0000056	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-2.2
PROVEAN	Benign	0.19	N
REVEL	Benign	0.049
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.032
MutPred		0.30		Gain of disorder (P = 0.0162);
MPC		0.032
ClinPred		0.010	T
GERP RS		-6.8
PromoterAI		-0.026	Neutral
Varity_R		0.046
gMVP		0.33
Mutation Taster		=96/4	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: rs3821242; hg19: chr2-234637803; COSMIC: COSV59383712;