chr2-233672032-T-C

Position:

• chr2-233672032-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021027.3(UGT1A9):​c.98T>C​(p.Met33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,136 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0091 (11 hom., cov: 32)
  • Exomes 𝑓: 0.012 (121 hom.)
• Consequence: UGT1A9 NM_021027.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.121

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 (MetaRNN=0.009270132).
• BP6: Variant 2-233672032-T-C is Benign according to our data. Variant chr2-233672032-T-C is described in ClinVar as [Benign]. Clinvar id is 2652019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A9	NM_021027.3	c.98T>C	p.Met33Thr	missense_variant	1/5	ENST00000354728.5
UGT1A10	NM_019075.4	c.855+34655T>C		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.855+53470T>C		intron_variant		ENST00000373450.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A9	ENST00000354728.5	c.98T>C	p.Met33Thr	missense_variant	1/5	1	NM_021027.3	P1
UGT1A10	ENST00000344644.10	c.855+34655T>C		intron_variant		1	NM_019075.4	P1
UGT1A8	ENST00000373450.5	c.855+53470T>C		intron_variant		1	NM_019076.5	P1
UGT1A10	ENST00000373445.1	c.855+34655T>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1381 AN: 152188 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00972 AC: 2443 AN: 251228 Hom.: 16 AF XY: 0.0101 AC XY: 1374 AN XY: 135750

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0117 AC: 17139 AN: 1461830 Hom.: 121 Cov.: 33 AF XY: 0.0117 AC XY: 8481 AN XY: 727202

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00223

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00905 AC: 1379 AN: 152306 Hom.: 11 Cov.: 32 AF XY: 0.00826 AC XY: 615 AN XY: 74466

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00989

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00865 Hom.: 8

Bravo AF: 0.00867

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0128 AC: 110

ExAC AF: 0.0109 AC: 1321

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

UGT1A9: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.0091	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D;D;D;N
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.065
Sift	Benign	0.70	T
Sift4G	Benign	0.39	T
Polyphen		0.096	B
Vest4		0.19
MPC		0.13
ClinPred		0.029	T
GERP RS		3.5
Varity_R		0.27
gMVP		0.30

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: rs72551330; hg19: chr2-234580678;