rs17863783

Positions:

• chr2-233693631-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001072.4(UGT1A6):​c.627G>T​(p.Val209=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,614,074 control chromosomes in the GnomAD database, including 1,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (380 hom., cov: 32)
  • Exomes 𝑓: 0.027 (815 hom.)
• Consequence: UGT1A6 NM_001072.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0120

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-233693631-G-T is Benign according to our data. Variant chr2-233693631-G-T is described in ClinVar as [Benign]. Clinvar id is 440382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-233693631-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.012 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A6	NM_001072.4	c.627G>T	p.Val209=	synonymous_variant	1/5	ENST00000305139.11
UGT1A10	NM_019075.4	c.855+56254G>T		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-73403G>T		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.855+10839G>T		intron_variant		ENST00000373426.4
UGT1A9	NM_021027.3	c.855+20842G>T		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A6	ENST00000305139.11	c.627G>T	p.Val209=	synonymous_variant	1/5	1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.855+56254G>T		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+20842G>T		intron_variant		1	NM_021027.3	P1
UGT1A7	ENST00000373426.4	c.855+10839G>T		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-73403G>T		intron_variant		1	NM_019076.5	P1
	ENST00000439336.1	n.466C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8241 AN: 152082 Hom.: 379 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0670

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0287

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.0422

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0555

GnomAD3 exomes AF: 0.0379 AC: 9522 AN: 251128 Hom.: 289 AF XY: 0.0357 AC XY: 4848 AN XY: 135714

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0213

Gnomad EAS exome AF: 0.0324

Gnomad SAS exome AF: 0.0418

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0333

GnomAD4 exome AF: 0.0267 AC: 39032 AN: 1461874 Hom.: 815 Cov.: 34 AF XY: 0.0267 AC XY: 19403 AN XY: 727236

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0578

Gnomad4 ASJ exome AF: 0.0249

Gnomad4 EAS exome AF: 0.0197

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0396

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0543 AC: 8262 AN: 152200 Hom.: 380 Cov.: 32 AF XY: 0.0552 AC XY: 4108 AN XY: 74424

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0673

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.0290

Gnomad4 SAS AF: 0.0428

Gnomad4 FIN AF: 0.0422

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0277 Hom.: 257

Bravo AF: 0.0587

Asia WGS AF: 0.0490 AC: 169 AN: 3478

EpiCase AF: 0.0210

EpiControl AF: 0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2019	This variant is associated with the following publications: (PMID: 22939045, 22228101) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	16
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17863783; hg19: chr2-234602277; COSMIC: COSV59395092; COSMIC: COSV59395092;