2-233729266-T-C

Position:

• chr2-233729266-T-C

Variant summary

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

The NM_019093.4(UGT1A3):​c.140T>C​(p.Val47Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,613,866 control chromosomes in the GnomAD database, including 130,866 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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 0.46 (17326 hom., cov: 32)
  • Exomes 𝑓: 0.39 (113540 hom.)
• Consequence: UGT1A3 NM_019093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.237

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=9.600021E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A3	NM_019093.4	c.140T>C	p.Val47Ala	missense_variant	1/5	ENST00000482026.6
UGT1A6	NM_001072.4	c.861+35401T>C		intron_variant		ENST00000305139.11
UGT1A4	NM_007120.3	c.867+9579T>C		intron_variant		ENST00000373409.8
UGT1A10	NM_019075.4	c.856-37768T>C		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-37768T>C		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.856-37768T>C		intron_variant		ENST00000373426.4
UGT1A5	NM_019078.2	c.867+15408T>C		intron_variant		ENST00000373414.4
UGT1A9	NM_021027.3	c.856-37768T>C		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A3	ENST00000482026.6	c.140T>C	p.Val47Ala	missense_variant	1/5	1	NM_019093.4	P1
UGT1A6	ENST00000305139.11	c.861+35401T>C		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-37768T>C		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.856-37768T>C		intron_variant		1	NM_021027.3	P1
UGT1A4	ENST00000373409.8	c.867+9579T>C		intron_variant		1	NM_007120.3	P1
UGT1A5	ENST00000373414.4	c.867+15408T>C		intron_variant		1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.856-37768T>C		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-37768T>C		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69467 AN: 151914 Hom.: 17319 Cov.: 32

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.412

GnomAD3 exomes AF: 0.390 AC: 98106 AN: 251356 Hom.: 20671 AF XY: 0.389 AC XY: 52900 AN XY: 135854

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.427

Gnomad FIN exome AF: 0.433

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.388 AC: 566642 AN: 1461834 Hom.: 113540 Cov.: 107 AF XY: 0.388 AC XY: 282443 AN XY: 727210

Gnomad4 AFR exome AF: 0.670

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.426

Gnomad4 NFE exome AF: 0.384

Gnomad4 OTH exome AF: 0.393

GnomAD4 genome AF: 0.457 AC: 69507 AN: 152032 Hom.: 17326 Cov.: 32 AF XY: 0.453 AC XY: 33684 AN XY: 74314

Gnomad4 AFR AF: 0.666

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.418

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.406

Alfa AF: 0.405 Hom.: 6285

Bravo AF: 0.460

TwinsUK AF: 0.378 AC: 1401

ALSPAC AF: 0.391 AC: 1505

ESP6500AA AF: 0.660 AC: 2908

ESP6500EA AF: 0.392 AC: 3367

ExAC AF: 0.396 AC: 48044

Asia WGS AF: 0.289 AC: 1006 AN: 3478

EpiCase AF: 0.390

EpiControl AF: 0.389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.24
DANN	Benign	0.52
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	0.0000096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.064
MPC		0.027
ClinPred		0.018	T
GERP RS		-6.8
Varity_R		0.035
gMVP		0.57

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: rs6431625; hg19: chr2-234637912; COSMIC: COSV59389211;