rs17864686

chr2-233682693-G-A

Variant summary

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

The NM_019077.3(UGT1A7):c.756G>A(p.Leu252=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,613,738 control chromosomes in the GnomAD database, including 37,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2738 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34485 hom.)
• Consequence: UGT1A7 NM_019077.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.54

Genes affected

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]

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]

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-233682693-G-A is Benign according to our data. Variant chr2-233682693-G-A is described in ClinVar as [Benign]. Clinvar id is 440390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A7	NM_019077.3	c.756G>A	p.Leu252=	synonymous_variant	1/5	ENST00000373426.4
UGT1A10	NM_019075.4	c.855+45316G>A		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.855+64131G>A		intron_variant		ENST00000373450.5
UGT1A9	NM_021027.3	c.855+9904G>A		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A7	ENST00000373426.4	c.756G>A	p.Leu252=	synonymous_variant	1/5	1	NM_019077.3	P1
UGT1A10	ENST00000344644.10	c.855+45316G>A		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+9904G>A		intron_variant		1	NM_021027.3	P1
UGT1A8	ENST00000373450.5	c.855+64131G>A		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27595 AN: 152028 Hom.: 2732 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.198 AC: 49676 AN: 250998 Hom.: 5217 AF XY: 0.200 AC XY: 27087 AN XY: 135634

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.207

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.214 AC: 313247 AN: 1461592 Hom.: 34485 Cov.: 36 AF XY: 0.213 AC XY: 155185 AN XY: 727104

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.201

GnomAD4 genome AF: 0.182 AC: 27623 AN: 152146 Hom.: 2738 Cov.: 32 AF XY: 0.178 AC XY: 13272 AN XY: 74376

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.191

Alfa AF: 0.198 Hom.: 1811

Bravo AF: 0.174

Asia WGS AF: 0.200 AC: 693 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.216

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 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	5.4
Dann	Benign	0.73

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: rs17864686; hg19: chr2-234591339; COSMIC: COSV60831800;