chr2-233672357-T-G

Variant names:

• chr2-233672357-T-G
• rs138301590
• NM_021027.3:c.423T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_021027.3(UGT1A9):​c.423T>G​(p.Ser141Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000703 in 1,614,202 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (3 hom.)
• Consequence: UGT1A9 NM_021027.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.16
• Publications: 4 publications found

Genes affected

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]

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]

UGT1A (HGNC:12529):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-233672357-T-G is Benign according to our data. Variant chr2-233672357-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3041957.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.16 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A9	NM_021027.3	c.423T>G	p.Ser141Ser	synonymous_variant	Exon 1 of 5	ENST00000354728.5	NP_066307.1
UGT1A10	NM_019075.4	c.855+34980T>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.855+53795T>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A		n.233672357T>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A9	ENST00000354728.5	c.423T>G	p.Ser141Ser	synonymous_variant	Exon 1 of 5	1	NM_021027.3	ENSP00000346768.4
UGT1A10	ENST00000344644.10	c.855+34980T>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A8	ENST00000373450.5	c.855+53795T>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4
UGT1A10	ENST00000373445.1	c.855+34980T>G		intron_variant	Intron 1 of 4	1		ENSP00000362544.1

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00107 AC: 269 AN: 251190 AF XY: 0.000994

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000683 AC: 998 AN: 1461846 Hom.: 3 Cov.: 33 AF XY: 0.000644 AC XY: 468 AN XY: 727230

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00237 AC: 106 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000697 AC: 775 AN: 1111986

Other (OTH) AF: 0.00106 AC: 64 AN: 60388

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74506

African (AFR) AF: 0.000216 AC: 9 AN: 41582

American (AMR) AF: 0.00261 AC: 40 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68036

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000701 Hom.: 0

Bravo AF: 0.000982

EpiCase AF: 0.000763

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

UGT1A9-related disorder Benign:1

May 14, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	9.6
DANN	Benign	0.61
PhyloP100		-2.2
PromoterAI		0.0082	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138301590; hg19: chr2-234581003;