2-233729464-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_019093.4(UGT1A3):c.338G>C(p.Ser113Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: UGT1A3 NM_019093.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.11

Genes affected

UGT1A3 (HGNC:12535): (UDP glucuronosyltransferase family 1 member A3) 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. Substrates of this enzyme include estrone, 2-hydroxyestrone, and metabolites of benzo alpha-pyrene. [provided by RefSeq, Jul 2008]

UGT1A6 (HGNC:12538): (UDP glucuronosyltransferase family 1 member A6) 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 phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants. [provided by RefSeq, Jul 2008]

UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) 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. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [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]

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]

UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) 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. [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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004835844).
• BP6: Variant 2-233729464-G-C is Benign according to our data. Variant chr2-233729464-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3186098.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A3	NM_019093.4	c.338G>C	p.Ser113Thr	missense_variant	1/5	ENST00000482026.6
UGT1A6	NM_001072.4	c.861+35599G>C		intron_variant		ENST00000305139.11
UGT1A4	NM_007120.3	c.867+9777G>C		intron_variant		ENST00000373409.8
UGT1A10	NM_019075.4	c.856-37570G>C		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-37570G>C		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.856-37570G>C		intron_variant		ENST00000373426.4
UGT1A5	NM_019078.2	c.867+15606G>C		intron_variant		ENST00000373414.4
UGT1A9	NM_021027.3	c.856-37570G>C		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A3	ENST00000482026.6	c.338G>C	p.Ser113Thr	missense_variant	1/5	1	NM_019093.4	P1
UGT1A6	ENST00000305139.11	c.861+35599G>C		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-37570G>C		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.856-37570G>C		intron_variant		1	NM_021027.3	P1
UGT1A4	ENST00000373409.8	c.867+9777G>C		intron_variant		1	NM_007120.3	P1
UGT1A5	ENST00000373414.4	c.867+15606G>C		intron_variant		1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.856-37570G>C		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-37570G>C		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251362 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135842

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461818 Hom.: 0 Cov.: 97 AF XY: 0.0000440 AC XY: 32 AN XY: 727200

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.000523 AC XY: 39 AN XY: 74500

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000818 Hom.: 0

Bravo AF: 0.000752

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.0010
Dann	Benign	0.35
DEOGEN2	Benign	0.056	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	0.37	N
REVEL	Benign	0.025
Sift	Benign	0.63	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.28
MPC		0.024
ClinPred		0.018	T
GERP RS		-8.7
Varity_R		0.040
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146268573; hg19: chr2-234638110;