2-233713733-C-A

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
UGT1A5	NM_019078.2	c.742C>A	p.Leu248Ile	missense_variant	1/5	ENST00000373414.4
UGT1A6	NM_001072.4	c.861+19868C>A		intron_variant		ENST00000305139.11
UGT1A10	NM_019075.4	c.856-53301C>A		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-53301C>A		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.855+30941C>A		intron_variant		ENST00000373426.4
UGT1A9	NM_021027.3	c.855+40944C>A		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A5	ENST00000373414.4	c.742C>A	p.Leu248Ile	missense_variant	1/5	1	NM_019078.2	P1
UGT1A6	ENST00000305139.11	c.861+19868C>A		intron_variant		1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.856-53301C>A		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+40944C>A		intron_variant		1	NM_021027.3	P1
UGT1A7	ENST00000373426.4	c.855+30941C>A		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-53301C>A		intron_variant		1	NM_019076.5	P1

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

GnomAD3 exomes AF: 0.0745 AC: 16898 AN: 226710 Hom.: 1915 AF XY: 0.0744 AC XY: 9052 AN XY: 121588

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 SAS exome AF: 0.129

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

Gnomad4 AFR exome AF: 0.0953

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0888

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.0689

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0985

GnomAD4 genome AF: 0.101 AC: 15381 AN: 152028 Hom.: 882 Cov.: 32 AF XY: 0.102 AC XY: 7580 AN XY: 74324

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0599

Gnomad4 NFE AF: 0.0901

Gnomad4 OTH AF: 0.116

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 08, 2018

- -

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
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
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

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: rs2012736; hg19: chr2-234622379; COSMIC: COSV59382190;