chr2-233743701-C-G

Position:

• chr2-233743701-C-G

Variant summary

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

The NM_007120.3(UGT1A4):​c.868-23333C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,367,248 control chromosomes in the GnomAD database, including 43,102 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 0.19 (3494 hom., cov: 33)
  • Exomes 𝑓: 0.25 (39608 hom.)
• Consequence: UGT1A4 NM_007120.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.57

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]

UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) 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. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [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]

UGT1A3 (HGNC:12535): (UDP glucuronosyltransferase family 1 member A3) 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. Substrates of this enzyme include estrone, 2-hydroxyestrone, and metabolites of benzo alpha-pyrene. [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]

DNAJB3 (HGNC:32397): (DnaJ heat shock protein family (Hsp40) member B3) Predicted to be located in acrosomal vesicle and centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A6	NM_001072.4	c.862-23333C>G		intron_variant		ENST00000305139.11
UGT1A4	NM_007120.3	c.868-23333C>G		intron_variant		ENST00000373409.8
UGT1A10	NM_019075.4	c.856-23333C>G		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-23333C>G		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.856-23333C>G		intron_variant		ENST00000373426.4
UGT1A5	NM_019078.2	c.868-23333C>G		intron_variant		ENST00000373414.4
UGT1A3	NM_019093.4	c.867+13708C>G		intron_variant		ENST00000482026.6
UGT1A9	NM_021027.3	c.856-23333C>G		intron_variant		ENST00000354728.5
DNAJB3	NR_172931.1	n.298G>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A6	ENST00000305139.11	c.862-23333C>G		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-23333C>G		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.856-23333C>G		intron_variant		1	NM_021027.3	P1
UGT1A4	ENST00000373409.8	c.868-23333C>G		intron_variant		1	NM_007120.3	P1
UGT1A5	ENST00000373414.4	c.868-23333C>G		intron_variant		1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.856-23333C>G		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-23333C>G		intron_variant		1	NM_019076.5	P1
UGT1A3	ENST00000482026.6	c.867+13708C>G		intron_variant		1	NM_019093.4	P1
DNAJB3	ENST00000446806.1	n.216G>C		non_coding_transcript_exon_variant	1/1
DNAJB3	ENST00000449667.1	n.315G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28501 AN: 151852 Hom.: 3501 Cov.: 33

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.0424

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.219 AC: 54568 AN: 248990 Hom.: 7219 AF XY: 0.231 AC XY: 31252 AN XY: 135146

Gnomad AFR exome AF: 0.0479

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.263

Gnomad EAS exome AF: 0.0430

Gnomad SAS exome AF: 0.307

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.249 AC: 302289 AN: 1215278 Hom.: 39608 Cov.: 33 AF XY: 0.253 AC XY: 152178 AN XY: 602284

Gnomad4 AFR exome AF: 0.0442

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.0408

Gnomad4 SAS exome AF: 0.305

Gnomad4 FIN exome AF: 0.309

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.187 AC: 28488 AN: 151970 Hom.: 3494 Cov.: 33 AF XY: 0.191 AC XY: 14196 AN XY: 74312

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.0427

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.178

Alfa AF: 0.231 Hom.: 3372

Bravo AF: 0.167

Asia WGS AF: 0.156 AC: 544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0060
DANN	Benign	0.59

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: rs13009407; hg19: chr2-234652347; COSMIC: COSV59395115; COSMIC: COSV59395115;