2-233713733-C-A

Variant names:

• chr2-233713733-C-A
• rs2012736
• NM_019078.2:c.742C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_019078.2(UGT1A5):​c.742C>A​(p.Leu248Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 1,587,018 control chromosomes in the GnomAD database, including 8,662 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (882 hom., cov: 32)
  • Exomes 𝑓: 0.090 (7780 hom.)
• Consequence: UGT1A5 NM_019078.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.82

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5624037E-4).
• BP6: Variant 2-233713733-C-A is Benign according to our data. Variant chr2-233713733-C-A is described in ClinVar as [Benign]. Clinvar id is 770344.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.742C>A	p.Leu248Ile	missense_variant	Exon 1 of 5	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+19868C>A		intron_variant	Intron 1 of 4	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-53301C>A		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-53301C>A		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+30941C>A		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+40944C>A		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.742C>A	p.Leu248Ile	missense_variant	Exon 1 of 5	1	NM_019078.2	ENSP00000362513.3
UGT1A6	ENST00000305139.11	c.861+19868C>A		intron_variant	Intron 1 of 4	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.856-53301C>A		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+40944C>A		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.855+30941C>A		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-53301C>A		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15361 AN: 151910 Hom.: 878 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0599

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0901

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.0745 AC: 16898 AN: 226710 AF XY: 0.0744

Gnomad AFR exome AF: 0.0698

Gnomad AMR exome AF: 0.0781

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0534

Gnomad OTH exome AF: 0.0688

GnomAD4 exome AF: 0.0898 AC: 128894 AN: 1434990 Hom.: 7780 Cov.: 34 AF XY: 0.0922 AC XY: 65667 AN XY: 712590

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

African (AFR) AF: 0.0953 AC: 3132 AN: 32854

American (AMR) AF: 0.109 AC: 4689 AN: 42916

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 2241 AN: 25232

East Asian (EAS) AF: 0.164 AC: 6437 AN: 39288

South Asian (SAS) AF: 0.180 AC: 14855 AN: 82322

European-Finnish (FIN) AF: 0.0689 AC: 3652 AN: 53038

Middle Eastern (MID) AF: 0.130 AC: 732 AN: 5616

European-Non Finnish (NFE) AF: 0.0798 AC: 87314 AN: 1094414

Other (OTH) AF: 0.0985 AC: 5842 AN: 59310

⚠️ 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: 15381 AN: 152028 Hom.: 882 Cov.: 32 AF XY: 0.102 AC XY: 7580 AN XY: 74324

African (AFR) AF: 0.104 AC: 4309 AN: 41484

American (AMR) AF: 0.111 AC: 1700 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1042 AN: 5142

South Asian (SAS) AF: 0.194 AC: 930 AN: 4800

European-Finnish (FIN) AF: 0.0599 AC: 634 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0901 AC: 6121 AN: 67966

Other (OTH) AF: 0.116 AC: 245 AN: 2112

Alfa AF: 0.0703 Hom.: 253

Bravo AF: 0.103

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.0270 AC: 232

ExAC AF: 0.116 AC: 14080

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0010
DANN	Benign	0.45
DEOGEN2	Benign	0.089	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.00026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		-1.8
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.16
Sift	Benign	0.32	T
Sift4G	Benign	0.42	T
Polyphen		0.0020	B
Vest4		0.025
MPC		0.18
ClinPred		0.012	T
GERP RS		-9.6
Varity_R		0.070
gMVP		0.29
Mutation Taster		=90/10	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: rs2012736; hg19: chr2-234622379; COSMIC: COSV59382190;