rs2070959

Positions:

• chr2-233693545-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001072.4(UGT1A6):​c.541A>G​(p.Thr181Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,613,956 control chromosomes in the GnomAD database, including 84,631 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (7183 hom., cov: 32)
  • Exomes 𝑓: 0.32 (77448 hom.)
• Consequence: UGT1A6 NM_001072.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.39

Genes affected

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.784929E-4).
• BP6: Variant 2-233693545-A-G is Benign according to our data. Variant chr2-233693545-A-G is described in ClinVar as [Benign]. Clinvar id is 440381.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A6	NM_001072.4	c.541A>G	p.Thr181Ala	missense_variant	1/5	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.855+56168A>G		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-73489A>G		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+10753A>G		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+20756A>G		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A6	ENST00000305139.11	c.541A>G	p.Thr181Ala	missense_variant	1/5	1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.855+56168A>G		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.855+20756A>G		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A7	ENST00000373426.4	c.855+10753A>G		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-73489A>G		intron_variant		1	NM_019076.5	ENSP00000362549	P1
	ENST00000439336.1	n.552T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45649 AN: 151972 Hom.: 7190 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.277

GnomAD3 exomes AF: 0.312 AC: 78275 AN: 251278 Hom.: 13226 AF XY: 0.323 AC XY: 43809 AN XY: 135784

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.194

Gnomad SAS exome AF: 0.401

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.321 AC: 469827 AN: 1461866 Hom.: 77448 Cov.: 93 AF XY: 0.326 AC XY: 236811 AN XY: 727226

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.400

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.401

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.320

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.300 AC: 45648 AN: 152090 Hom.: 7183 Cov.: 32 AF XY: 0.307 AC XY: 22798 AN XY: 74364

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.397

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.400

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.276

Alfa AF: 0.321 Hom.: 19875

Bravo AF: 0.279

TwinsUK AF: 0.309 AC: 1145

ALSPAC AF: 0.329 AC: 1267

ESP6500AA AF: 0.252 AC: 1110

ESP6500EA AF: 0.332 AC: 2852

ExAC AF: 0.313 AC: 38033

Asia WGS AF: 0.277 AC: 969 AN: 3478

EpiCase AF: 0.335

EpiControl AF: 0.332

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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.088
DANN	Benign	0.44
DEOGEN2	Benign	0.0052	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.00058	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.085	.;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.054
Sift	Benign	0.73	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.0	.;B
Vest4		0.015
MPC		0.098
ClinPred		0.0083	T
GERP RS		-9.4
Varity_R		0.022
gMVP		0.25

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: rs2070959; hg19: chr2-234602191; COSMIC: COSV59383870; COSMIC: COSV59383870;