2-233713774-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_019078.2(UGT1A5):c.783T>C(p.Phe261=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0899 in 1,583,730 control chromosomes in the GnomAD database, including 8,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (893 hom., cov: 32)
  • Exomes 𝑓: 0.089 (7726 hom.)
• Consequence: UGT1A5 NM_019078.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26

Genes affected

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]

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]

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-233713774-T-C is Benign according to our data. Variant chr2-233713774-T-C is described in ClinVar as [Benign]. Clinvar id is 770347.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A5	NM_019078.2	c.783T>C	p.Phe261=	synonymous_variant	1/5	ENST00000373414.4
UGT1A6	NM_001072.4	c.861+19909T>C		intron_variant		ENST00000305139.11
UGT1A10	NM_019075.4	c.856-53260T>C		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-53260T>C		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.855+30982T>C		intron_variant		ENST00000373426.4
UGT1A9	NM_021027.3	c.855+40985T>C		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A5	ENST00000373414.4	c.783T>C	p.Phe261=	synonymous_variant	1/5	1	NM_019078.2	P1
UGT1A6	ENST00000305139.11	c.861+19909T>C		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-53260T>C		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+40985T>C		intron_variant		1	NM_021027.3	P1
UGT1A7	ENST00000373426.4	c.855+30982T>C		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-53260T>C		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15397 AN: 152036 Hom.: 889 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0600

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0676 AC: 15120 AN: 223634 Hom.: 1837 AF XY: 0.0671 AC XY: 8047 AN XY: 119862

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.0729

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0457

Gnomad OTH exome AF: 0.0661

GnomAD4 exome AF: 0.0887 AC: 127030 AN: 1431576 Hom.: 7726 Cov.: 34 AF XY: 0.0910 AC XY: 64704 AN XY: 710860

Gnomad4 AFR exome AF: 0.0958

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0887

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.0676

Gnomad4 NFE exome AF: 0.0789

Gnomad4 OTH exome AF: 0.0975

GnomAD4 genome AF: 0.101 AC: 15417 AN: 152154 Hom.: 893 Cov.: 32 AF XY: 0.102 AC XY: 7601 AN XY: 74382

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0600

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0918 Hom.: 253

Bravo AF: 0.103

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

Invitae

Jun 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.6
Dann	Benign	0.71

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: rs17862869; hg19: chr2-234622420; COSMIC: COSV59382214;