2-233713774-T-C

Variant names:

• chr2-233713774-T-C
• rs17862869
• NM_019078.2:c.783T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_019078.2(UGT1A5):​c.783T>C​(p.Phe261Phe) 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]

UGT1A (HGNC:12529):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
UGT1A5	NM_019078.2	c.783T>C	p.Phe261Phe	synonymous_variant	Exon 1 of 5	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+19909T>C		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-53260T>C		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-53260T>C		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+30982T>C		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+40985T>C		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A5	ENST00000373414.4	c.783T>C	p.Phe261Phe	synonymous_variant	Exon 1 of 5	1	NM_019078.2	ENSP00000362513.3
UGT1A6	ENST00000305139.11	c.861+19909T>C		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-53260T>C		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+40985T>C		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.855+30982T>C		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-53260T>C		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

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

GnomAD2 exomes AF: 0.0676 AC: 15120 AN: 223634 AF XY: 0.0671

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0958 AC: 3151 AN: 32898

American (AMR) AF: 0.104 AC: 4415 AN: 42386

Ashkenazi Jewish (ASJ) AF: 0.0887 AC: 2239 AN: 25248

East Asian (EAS) AF: 0.159 AC: 6148 AN: 38724

South Asian (SAS) AF: 0.180 AC: 14869 AN: 82378

European-Finnish (FIN) AF: 0.0676 AC: 3574 AN: 52886

Middle Eastern (MID) AF: 0.127 AC: 707 AN: 5570

European-Non Finnish (NFE) AF: 0.0789 AC: 86156 AN: 1092302

Other (OTH) AF: 0.0975 AC: 5771 AN: 59184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.104 AC: 4317 AN: 41516

American (AMR) AF: 0.112 AC: 1707 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3468

East Asian (EAS) AF: 0.203 AC: 1043 AN: 5148

South Asian (SAS) AF: 0.194 AC: 936 AN: 4818

European-Finnish (FIN) AF: 0.0600 AC: 636 AN: 10594

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6133 AN: 67994

Other (OTH) AF: 0.116 AC: 246 AN: 2114

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

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.6
DANN	Benign	0.71
PhyloP100		1.3
Mutation Taster		=94/6	polymorphism (auto)

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

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Other links and lift over

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