2-233729599-C-T

Variant summary

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

The NM_019093.4(UGT1A3):c.473C>T(p.Ala158Val) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,614,002 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A158T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: UGT1A3 NM_019093.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.01

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009344965).
• BP6: Variant 2-233729599-C-T is Benign according to our data. Variant chr2-233729599-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 789161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A3	NM_019093.4	c.473C>T	p.Ala158Val	missense_variant	1/5	ENST00000482026.6
UGT1A6	NM_001072.4	c.861+35734C>T		intron_variant		ENST00000305139.11
UGT1A4	NM_007120.3	c.867+9912C>T		intron_variant		ENST00000373409.8
UGT1A10	NM_019075.4	c.856-37435C>T		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-37435C>T		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.856-37435C>T		intron_variant		ENST00000373426.4
UGT1A5	NM_019078.2	c.867+15741C>T		intron_variant		ENST00000373414.4
UGT1A9	NM_021027.3	c.856-37435C>T		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A3	ENST00000482026.6	c.473C>T	p.Ala158Val	missense_variant	1/5	1	NM_019093.4	P1
UGT1A6	ENST00000305139.11	c.861+35734C>T		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-37435C>T		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.856-37435C>T		intron_variant		1	NM_021027.3	P1
UGT1A4	ENST00000373409.8	c.867+9912C>T		intron_variant		1	NM_007120.3	P1
UGT1A5	ENST00000373414.4	c.867+15741C>T		intron_variant		1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.856-37435C>T		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-37435C>T		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152142 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00214 AC: 537 AN: 251268 Hom.: 2 AF XY: 0.00194 AC XY: 263 AN XY: 135796

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00271 AC: 3968 AN: 1461742 Hom.: 8 Cov.: 98 AF XY: 0.00266 AC XY: 1936 AN XY: 727176

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152260 Hom.: 1 Cov.: 33 AF XY: 0.00222 AC XY: 165 AN XY: 74466

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00231

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00212 AC: 257

EpiCase AF: 0.00224

EpiControl AF: 0.00267

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	D;D;N;D;D;D;D;D;D;D;D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.36	B
Vest4		0.25
MVP		0.70
MPC		0.054
ClinPred		0.082	T
GERP RS		3.5
Varity_R		0.30
gMVP		0.51

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: rs61764030; hg19: chr2-234638245; COSMIC: COSV99043551;