chr2-233672357-T-G

Position:

• chr2-233672357-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_021027.3(UGT1A9):​c.423T>G​(p.Ser141=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
UGT1A9	NM_021027.3	c.423T>G	p.Ser141=	synonymous_variant	1/5	ENST00000354728.5	NP_066307.1
UGT1A10	NM_019075.4	c.855+34980T>G		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.855+53795T>G		intron_variant		ENST00000373450.5	NP_061949.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A9	ENST00000354728.5	c.423T>G	p.Ser141=	synonymous_variant	1/5	1	NM_021027.3	ENSP00000346768	P1
UGT1A10	ENST00000344644.10	c.855+34980T>G		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A8	ENST00000373450.5	c.855+53795T>G		intron_variant		1	NM_019076.5	ENSP00000362549	P1
UGT1A10	ENST00000373445.1	c.855+34980T>G		intron_variant		1		ENSP00000362544

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

GnomAD3 exomes AF: 0.00107 AC: 269 AN: 251190 Hom.: 1 AF XY: 0.000994 AC XY: 135 AN XY: 135748

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 SAS 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

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.000697

Gnomad4 OTH exome AF: 0.00106

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

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00237

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2019

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs138301590; hg19: chr2-234581003;