2-233681881-T-G

Position:

• chr2-233681881-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_019075.4(UGT1A10):​c.855+44504T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,551,906 control chromosomes in the GnomAD database, including 111,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.34 (9238 hom., cov: 33)
  • Exomes 𝑓: 0.38 (102541 hom.)
• Consequence: UGT1A10 NM_019075.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.21

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-233681881-T-G is Benign according to our data. Variant chr2-233681881-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440384.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A10	NM_019075.4	c.855+44504T>G		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.855+63319T>G		intron_variant		ENST00000373450.5
UGT1A9	NM_021027.3	c.855+9092T>G		intron_variant		ENST00000354728.5
UGT1A7	NM_019077.3			upstream_gene_variant		ENST00000373426.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A10	ENST00000344644.10	c.855+44504T>G		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+9092T>G		intron_variant		1	NM_021027.3	P1
UGT1A8	ENST00000373450.5	c.855+63319T>G		intron_variant		1	NM_019076.5	P1
UGT1A7	ENST00000373426.4			upstream_gene_variant		1	NM_019077.3	P1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51829 AN: 151996 Hom.: 9245 Cov.: 33

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.317

GnomAD4 exome AF: 0.379 AC: 530386 AN: 1399792 Hom.: 102541 Cov.: 43 AF XY: 0.381 AC XY: 263151 AN XY: 690268

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.451

Gnomad4 NFE exome AF: 0.386

Gnomad4 OTH exome AF: 0.369

GnomAD4 genome AF: 0.341 AC: 51827 AN: 152114 Hom.: 9238 Cov.: 33 AF XY: 0.344 AC XY: 25606 AN XY: 74354

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.315

Alfa AF: 0.351 Hom.: 7022

Bravo AF: 0.320

Asia WGS AF: 0.287 AC: 1004 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 26202972, 15716465) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.083
DANN	Benign	0.41

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: rs7586110; hg19: chr2-234590527; COSMIC: COSV60838074; COSMIC: COSV60838074;