rs45449995

chr2-233729934-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_019093.4(UGT1A3):c.808A>G(p.Met270Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,614,076 control chromosomes in the GnomAD database, including 771 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 0.034 (101 hom., cov: 32)
  • Exomes 𝑓: 0.029 (670 hom.)
• Consequence: UGT1A3 NM_019093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41

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=0.011752695).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0336 (5124/152342) while in subpopulation AFR AF= 0.0506 (2104/41576). AF 95% confidence interval is 0.0488. There are 101 homozygotes in gnomad4. There are 2409 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 101 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A3	NM_019093.4	c.808A>G	p.Met270Val	missense_variant	1/5	ENST00000482026.6
UGT1A6	NM_001072.4	c.861+36069A>G		intron_variant		ENST00000305139.11
UGT1A4	NM_007120.3	c.867+10247A>G		intron_variant		ENST00000373409.8
UGT1A10	NM_019075.4	c.856-37100A>G		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-37100A>G		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.856-37100A>G		intron_variant		ENST00000373426.4
UGT1A5	NM_019078.2	c.867+16076A>G		intron_variant		ENST00000373414.4
UGT1A9	NM_021027.3	c.856-37100A>G		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A3	ENST00000482026.6	c.808A>G	p.Met270Val	missense_variant	1/5	1	NM_019093.4	P1
UGT1A6	ENST00000305139.11	c.861+36069A>G		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-37100A>G		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.856-37100A>G		intron_variant		1	NM_021027.3	P1
UGT1A4	ENST00000373409.8	c.867+10247A>G		intron_variant		1	NM_007120.3	P1
UGT1A5	ENST00000373414.4	c.867+16076A>G		intron_variant		1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.856-37100A>G		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-37100A>G		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5114 AN: 152224 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0263 AC: 6615 AN: 251282 Hom.: 103 AF XY: 0.0265 AC XY: 3599 AN XY: 135814

Gnomad AFR exome AF: 0.0465

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0448

Gnomad EAS exome AF: 0.00223

Gnomad SAS exome AF: 0.0209

Gnomad FIN exome AF: 0.0210

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0289 AC: 42302 AN: 1461734 Hom.: 670 Cov.: 108 AF XY: 0.0288 AC XY: 20939 AN XY: 727170

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0454

Gnomad4 EAS exome AF: 0.00108

Gnomad4 SAS exome AF: 0.0198

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0286

GnomAD4 genome AF: 0.0336 AC: 5124 AN: 152342 Hom.: 101 Cov.: 32 AF XY: 0.0323 AC XY: 2409 AN XY: 74498

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.0315

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.0306 Hom.: 64

Bravo AF: 0.0339

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.0542 AC: 239

ESP6500EA AF: 0.0310 AC: 267

ExAC AF: 0.0267 AC: 3247

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0329

EpiControl AF: 0.0315

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.89	P
Vest4		0.27
MPC		0.20
ClinPred		0.038	T
GERP RS		4.0
Varity_R		0.84
gMVP		0.43

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: rs45449995; hg19: chr2-234638580;