2-233718962-T-G

Variant names:

• chr2-233718962-T-G
• rs2011425
• NM_007120.3:c.142T>G

Variant summary

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

The NM_007120.3(UGT1A4):​c.142T>G​(p.Leu48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 1,614,090 control chromosomes in the GnomAD database, including 8,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.098 (854 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7362 hom.)
• Consequence: UGT1A4 NM_007120.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.291
• Publications: 110 publications found

Genes affected

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=0.0039671957).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A4	NM_007120.3	c.142T>G	p.Leu48Val	missense_variant	Exon 1 of 5	ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.867+5104T>G		intron_variant	Intron 1 of 4	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+25097T>G		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-48072T>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-48072T>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+36170T>G		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+46173T>G		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8	c.142T>G	p.Leu48Val	missense_variant	Exon 1 of 5	1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.867+5104T>G		intron_variant	Intron 1 of 4	1	NM_019078.2	ENSP00000362513.3
UGT1A6	ENST00000305139.11	c.861+25097T>G		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-48072T>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+46173T>G		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.855+36170T>G		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-48072T>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14840 AN: 152144 Hom.: 849 Cov.: 33

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0869

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.113 AC: 28517 AN: 251410 AF XY: 0.117

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.0522

Gnomad NFE exome AF: 0.0876

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0939 AC: 137332 AN: 1461828 Hom.: 7362 Cov.: 34 AF XY: 0.0972 AC XY: 70670 AN XY: 727216

African (AFR) AF: 0.101 AC: 3370 AN: 33476

American (AMR) AF: 0.123 AC: 5501 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2681 AN: 26136

East Asian (EAS) AF: 0.168 AC: 6665 AN: 39698

South Asian (SAS) AF: 0.194 AC: 16731 AN: 86254

European-Finnish (FIN) AF: 0.0585 AC: 3126 AN: 53418

Middle Eastern (MID) AF: 0.140 AC: 806 AN: 5764

European-Non Finnish (NFE) AF: 0.0829 AC: 92198 AN: 1111978

Other (OTH) AF: 0.104 AC: 6254 AN: 60390

GnomAD4 genome AF: 0.0976 AC: 14865 AN: 152262 Hom.: 854 Cov.: 33 AF XY: 0.0986 AC XY: 7338 AN XY: 74452

African (AFR) AF: 0.100 AC: 4173 AN: 41544

American (AMR) AF: 0.110 AC: 1684 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3470

East Asian (EAS) AF: 0.194 AC: 1002 AN: 5170

South Asian (SAS) AF: 0.194 AC: 934 AN: 4814

European-Finnish (FIN) AF: 0.0483 AC: 513 AN: 10616

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0869 AC: 5911 AN: 68022

Other (OTH) AF: 0.117 AC: 247 AN: 2116

Alfa AF: 0.0803 Hom.: 249

Bravo AF: 0.100

TwinsUK AF: 0.0785 AC: 291

ALSPAC AF: 0.0804 AC: 310

ESP6500AA AF: 0.0987 AC: 435

ESP6500EA AF: 0.0828 AC: 712

ExAC AF: 0.116 AC: 14077

Asia WGS AF: 0.191 AC: 662 AN: 3476

EpiCase AF: 0.0924

EpiControl AF: 0.0916

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.55
DANN	Benign	0.56
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.014	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.31	N
PhyloP100		-0.29
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.053
Sift	Benign	0.96	T
Sift4G	Benign	0.81	T
Vest4		0.056
ClinPred		0.00073	T
GERP RS		2.3
PromoterAI		-0.014	Neutral
Varity_R		0.032
gMVP		0.35
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2011425; hg19: chr2-234627608; COSMIC: COSV59387722; COSMIC: COSV59387722;