2-233681881-T-G

Variant names:

• chr2-233681881-T-G
• rs7586110
• NM_019075.4:c.855+44504T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 49 publications found

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]

UGT1A (HGNC:12529):

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

Our verdict: Benign. The variant received -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 VariationId is 440384.
• 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 rank	MANE	Protein	UniProt
UGT1A10	NM_019075.4	c.855+44504T>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.855+63319T>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A9	NM_021027.3	c.855+9092T>G		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1
UGT1A7	NM_019077.3	c.-57T>G		upstream_gene_variant		ENST00000373426.4	NP_061950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A10	ENST00000344644.10	c.855+44504T>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+9092T>G		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A8	ENST00000373450.5	c.855+63319T>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4
UGT1A7	ENST00000373426.4	c.-57T>G		upstream_gene_variant		1	NM_019077.3	ENSP00000362525.3

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

African (AFR) AF: 0.268 AC: 8363 AN: 31242

American (AMR) AF: 0.215 AC: 7398 AN: 34408

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 9607 AN: 21874

East Asian (EAS) AF: 0.220 AC: 8630 AN: 39172

South Asian (SAS) AF: 0.415 AC: 31293 AN: 75454

European-Finnish (FIN) AF: 0.451 AC: 23017 AN: 51050

Middle Eastern (MID) AF: 0.396 AC: 2144 AN: 5410

European-Non Finnish (NFE) AF: 0.386 AC: 418662 AN: 1083518

Other (OTH) AF: 0.369 AC: 21272 AN: 57664

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

African (AFR) AF: 0.266 AC: 11021 AN: 41502

American (AMR) AF: 0.271 AC: 4152 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1524 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1051 AN: 5178

South Asian (SAS) AF: 0.412 AC: 1984 AN: 4812

European-Finnish (FIN) AF: 0.474 AC: 5012 AN: 10564

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25880 AN: 67980

Other (OTH) AF: 0.315 AC: 663 AN: 2108

Alfa AF: 0.358 Hom.: 23419

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

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26202972, 15716465) -

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.083
DANN	Benign	0.41
PhyloP100		-3.2
PromoterAI		0.034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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