2-233693995-G-T

Variant summary

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

The NM_001072.4(UGT1A6):c.861+130G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,516,734 control chromosomes in the GnomAD database, including 2,435 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 0.064 (470 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1965 hom.)
• Consequence: UGT1A6 NM_001072.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326

Genes affected

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A6	NM_001072.4	c.861+130G>T		intron_variant		ENST00000305139.11
UGT1A10	NM_019075.4	c.855+56618G>T		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-73039G>T		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.855+11203G>T		intron_variant		ENST00000373426.4
UGT1A9	NM_021027.3	c.855+21206G>T		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A6	ENST00000305139.11	c.861+130G>T		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.855+56618G>T		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+21206G>T		intron_variant		1	NM_021027.3	P1
UGT1A7	ENST00000373426.4	c.855+11203G>T		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-73039G>T		intron_variant		1	NM_019076.5	P1
	ENST00000439336.1	n.260-158C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9713 AN: 152060 Hom.: 471 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0701

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.0824

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0618

GnomAD4 exome AF: 0.0373 AC: 50954 AN: 1364556 Hom.: 1965 AF XY: 0.0385 AC XY: 26027 AN XY: 676542

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.0412

Gnomad4 ASJ exome AF: 0.0695

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.0729

Gnomad4 FIN exome AF: 0.0751

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0452

GnomAD4 genome AF: 0.0638 AC: 9716 AN: 152178 Hom.: 470 Cov.: 32 AF XY: 0.0666 AC XY: 4958 AN XY: 74390

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0407

Gnomad4 ASJ AF: 0.0701

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.0700

Gnomad4 FIN AF: 0.0824

Gnomad4 NFE AF: 0.0276

Gnomad4 OTH AF: 0.0607

Alfa AF: 0.0208 Hom.: 11

Bravo AF: 0.0643

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.1
Dann	Benign	0.58

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: rs7592281; hg19: chr2-234602641; COSMIC: COSV59396015; COSMIC: COSV59396015;