rs4148329

Variant names:

• chr2-233773416-C-T
• rs4148329
• NM_007120.3:c.*857C>T

Variant summary

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

The NM_007120.3(UGT1A4):​c.*857C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 152,080 control chromosomes in the GnomAD database, including 20,947 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.

• Frequency:
  • Genomes: 𝑓 0.51 (20946 hom., cov: 33)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: UGT1A4 NM_007120.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06

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]

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]

UGT1A1 (HGNC:12530): (UDP glucuronosyltransferase family 1 member A1) 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 preferred substrate of this enzyme is bilirubin, although it also has moderate activity with simple phenols, flavones, and C18 steroids. Mutations in this gene result in Crigler-Najjar syndromes types I and II and in Gilbert syndrome. [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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A4	NM_007120.3	c.*857C>T		downstream_gene_variant		ENST00000373409.8	NP_009051.1
UGT1A5	NM_019078.2	c.*857C>T		downstream_gene_variant		ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.*857C>T		downstream_gene_variant		ENST00000482026.6	NP_061966.1
UGT1A1	NM_000463.3	c.*857C>T		downstream_gene_variant		ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4	c.*857C>T		downstream_gene_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.*857C>T		downstream_gene_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.*857C>T		downstream_gene_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.*857C>T		downstream_gene_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.*857C>T		downstream_gene_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8	c.*857C>T		downstream_gene_variant		1	NM_007120.3	ENSP00000362508.4
UGT1A5	ENST00000373414.4	c.*857C>T		downstream_gene_variant		1	NM_019078.2	ENSP00000362513.3
UGT1A3	ENST00000482026.6	c.*857C>T		downstream_gene_variant		1	NM_019093.4	ENSP00000418532.1
UGT1A1	ENST00000305208.10	c.*857C>T		downstream_gene_variant		1	NM_000463.3	ENSP00000304845.5
UGT1A6	ENST00000305139.11	c.*857C>T		downstream_gene_variant		1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.*857C>T		downstream_gene_variant		1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.*857C>T		downstream_gene_variant		1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.*857C>T		downstream_gene_variant		1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.*857C>T		downstream_gene_variant		1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77240 AN: 151960 Hom.: 20948 Cov.: 33

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.499

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 FIN exome AF: 1.00

GnomAD4 genome AF: 0.508 AC: 77263 AN: 152078 Hom.: 20946 Cov.: 33 AF XY: 0.517 AC XY: 38432 AN XY: 74324

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.511

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.603

Gnomad4 FIN AF: 0.690

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.494

Alfa AF: 0.559 Hom.: 33978

Bravo AF: 0.487

Asia WGS AF: 0.594 AC: 2065 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4148329; hg19: chr2-234682062;