chr2-233693319-A-G

Position:

• chr2-233693319-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001072.4(UGT1A6):​c.315A>G​(p.Leu105Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,613,864 control chromosomes in the GnomAD database, including 100,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (9738 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90448 hom.)
• Consequence: UGT1A6 NM_001072.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.633

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]

UGT1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-233693319-A-G is Benign according to our data. Variant chr2-233693319-A-G is described in ClinVar as [Benign]. Clinvar id is 440379.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.633 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A6	NM_001072.4	c.315A>G	p.Leu105Leu	synonymous_variant	1/5	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.855+55942A>G		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-73715A>G		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+10527A>G		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+20530A>G		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A6	ENST00000305139.11	c.315A>G	p.Leu105Leu	synonymous_variant	1/5	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.855+55942A>G		intron_variant		1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+20530A>G		intron_variant		1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.855+10527A>G		intron_variant		1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-73715A>G		intron_variant		1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53863 AN: 151962 Hom.: 9740 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.349 AC: 87768 AN: 251154 Hom.: 16242 AF XY: 0.358 AC XY: 48665 AN XY: 135752

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.227

Gnomad SAS exome AF: 0.443

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.348 AC: 508766 AN: 1461784 Hom.: 90448 Cov.: 80 AF XY: 0.352 AC XY: 256180 AN XY: 727196

Gnomad4 AFR exome AF: 0.363

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.443

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.341

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.354 AC: 53881 AN: 152080 Hom.: 9738 Cov.: 32 AF XY: 0.362 AC XY: 26871 AN XY: 74320

Gnomad4 AFR AF: 0.358

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.423

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.489

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.331

Alfa AF: 0.349 Hom.: 22484

Bravo AF: 0.337

Asia WGS AF: 0.326 AC: 1137 AN: 3476

EpiCase AF: 0.356

EpiControl AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.0
DANN	Benign	0.50

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: rs1105880; hg19: chr2-234601965; COSMIC: COSV59381798; COSMIC: COSV59381798;