2-233729259-C-T

Position:

• chr2-233729259-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019093.4(UGT1A3):​c.133C>T​(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,614,078 control chromosomes in the GnomAD database, including 92 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0022 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (81 hom.)
• Consequence: UGT1A3 NM_019093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10

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]

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]

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]

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]

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005053729).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A3	NM_019093.4	c.133C>T	p.Arg45Trp	missense_variant	1/5	ENST00000482026.6	NP_061966.1
UGT1A6	NM_001072.4	c.861+35394C>T		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A4	NM_007120.3	c.867+9572C>T		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A10	NM_019075.4	c.856-37775C>T		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-37775C>T		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-37775C>T		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.867+15401C>T		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A9	NM_021027.3	c.856-37775C>T		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A3	ENST00000482026.6	c.133C>T	p.Arg45Trp	missense_variant	1/5	1	NM_019093.4	ENSP00000418532	P1
UGT1A6	ENST00000305139.11	c.861+35394C>T		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-37775C>T		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.856-37775C>T		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A4	ENST00000373409.8	c.867+9572C>T		intron_variant		1	NM_007120.3	ENSP00000362508	P1
UGT1A5	ENST00000373414.4	c.867+15401C>T		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.856-37775C>T		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-37775C>T		intron_variant		1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 337 AN: 152210 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00444 AC: 1117 AN: 251446 Hom.: 18 AF XY: 0.00420 AC XY: 571 AN XY: 135896

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0395

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00223 AC: 3264 AN: 1461750 Hom.: 81 Cov.: 106 AF XY: 0.00233 AC XY: 1695 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.0531

Gnomad4 SAS exome AF: 0.00307

Gnomad4 FIN exome AF: 0.00466

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152328 Hom.: 11 Cov.: 33 AF XY: 0.00265 AC XY: 197 AN XY: 74480

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0417

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.00209

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00427 AC: 518

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.068	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D;N;D;D;D;D;D;D;D;D
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.75
MPC		0.032
ClinPred		0.093	T
GERP RS		-3.5
Varity_R		0.37
gMVP		0.50

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: rs45625338; hg19: chr2-234637905; COSMIC: COSV59381334;