2-233718970-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_007120.3(UGT1A4):c.150G>C(p.Glu50Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000457 in 1,614,150 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: UGT1A4 NM_007120.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.38

Genes affected

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]

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]

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033675045).
• BP6: Variant 2-233718970-G-C is Benign according to our data. Variant chr2-233718970-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2672867.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A4	NM_007120.3	c.150G>C	p.Glu50Asp	missense_variant	1/5	ENST00000373409.8
UGT1A6	NM_001072.4	c.861+25105G>C		intron_variant		ENST00000305139.11
UGT1A10	NM_019075.4	c.856-48064G>C		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-48064G>C		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.855+36178G>C		intron_variant		ENST00000373426.4
UGT1A5	NM_019078.2	c.867+5112G>C		intron_variant		ENST00000373414.4
UGT1A9	NM_021027.3	c.855+46181G>C		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A4	ENST00000373409.8	c.150G>C	p.Glu50Asp	missense_variant	1/5	1	NM_007120.3	P1
UGT1A6	ENST00000305139.11	c.861+25105G>C		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-48064G>C		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+46181G>C		intron_variant		1	NM_021027.3	P1
UGT1A5	ENST00000373414.4	c.867+5112G>C		intron_variant		1	NM_019078.2	P1
UGT1A7	ENST00000373426.4	c.855+36178G>C		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-48064G>C		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000553 AC: 139 AN: 251444 Hom.: 0 AF XY: 0.000552 AC XY: 75 AN XY: 135914

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000454 AC: 663 AN: 1461814 Hom.: 1 Cov.: 33 AF XY: 0.000439 AC XY: 319 AN XY: 727196

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000372

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74502

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000618 AC: 75

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.000981

EpiControl AF: 0.000771

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

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

UGT1A4: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.036	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.025	D
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.52		Loss of disorder (P = 0.1278);
MVP		0.43
MPC		0.031
ClinPred		0.037	T
GERP RS		1.0
Varity_R		0.17
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs45510694; hg19: chr2-234627616;