2-233718658-G-A

Position:

• chr2-233718658-G-A

Variant summary

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

The ENST00000373414.4(UGT1A5):​c.867+4800G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 1,529,416 control chromosomes in the GnomAD database, including 7,812 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 0.10 (885 hom., cov: 33)
  • Exomes 𝑓: 0.094 (6927 hom.)
• Consequence: UGT1A5 ENST00000373414.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.422

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]

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]

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 = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A6	NM_001072.4	c.861+24793G>A		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-48376G>A		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-48376G>A		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+35866G>A		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.867+4800G>A		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A9	NM_021027.3	c.855+45869G>A		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A6	ENST00000305139.11	c.861+24793G>A		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-48376G>A		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.855+45869G>A		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A5	ENST00000373414.4	c.867+4800G>A		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.855+35866G>A		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-48376G>A		intron_variant		1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes AF: 0.0998 AC: 15186 AN: 152192 Hom.: 881 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0879

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0943 AC: 129878 AN: 1377106 Hom.: 6927 AF XY: 0.0973 AC XY: 65960 AN XY: 678018

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.0659

Gnomad4 NFE exome AF: 0.0838

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.0998 AC: 15206 AN: 152310 Hom.: 885 Cov.: 33 AF XY: 0.100 AC XY: 7483 AN XY: 74474

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.0527

Gnomad4 NFE AF: 0.0879

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0940 Hom.: 735

Bravo AF: 0.102

Asia WGS AF: 0.200 AC: 692 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	1.4
DANN	Benign	0.31

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: rs3732218; hg19: chr2-234627304; COSMIC: COSV59387741; COSMIC: COSV59387741;