rs2070959

Variant names:

• chr2-233693545-A-G
• rs2070959
• NM_001072.4:c.541A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP2 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• 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
• Publications: 173 publications found

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]

ENSG00000224814 (HGNC:):

UGT1A (HGNC:12529):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.027979 (below the threshold of 3.09). Trascript score misZ: 0.14503 (below the threshold of 3.09).
• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001072.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A6	NM_001072.4	MANE Select	c.541A>G	p.Thr181Ala	missense	Exon 1 of 5	NP_001063.2
	UGT1A10	NM_019075.4	MANE Select	c.855+56168A>G		intron	N/A	NP_061948.1	Q5DT02
	UGT1A8	NM_019076.5	MANE Select	c.856-73489A>G		intron	N/A	NP_061949.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT1A6	ENST00000305139.11	TSL:1 MANE Select	c.541A>G	p.Thr181Ala	missense	Exon 1 of 5	ENSP00000303174.6	P19224-1
	UGT1A10	ENST00000344644.10	TSL:1 MANE Select	c.855+56168A>G		intron	N/A	ENSP00000343838.5	Q9HAW8-1
	UGT1A9	ENST00000354728.5	TSL:1 MANE Select	c.855+20756A>G		intron	N/A	ENSP00000346768.4	O60656-1

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

GnomAD2 exomes AF: 0.312 AC: 78275 AN: 251278 AF XY: 0.323

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 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

African (AFR) AF: 0.246 AC: 8232 AN: 33480

American (AMR) AF: 0.178 AC: 7948 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10442 AN: 26136

East Asian (EAS) AF: 0.220 AC: 8722 AN: 39680

South Asian (SAS) AF: 0.401 AC: 34572 AN: 86258

European-Finnish (FIN) AF: 0.423 AC: 22590 AN: 53418

Middle Eastern (MID) AF: 0.340 AC: 1959 AN: 5768

European-Non Finnish (NFE) AF: 0.320 AC: 356328 AN: 1112008

Other (OTH) AF: 0.315 AC: 19034 AN: 60394

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

African (AFR) AF: 0.244 AC: 10107 AN: 41484

American (AMR) AF: 0.230 AC: 3519 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1379 AN: 3472

East Asian (EAS) AF: 0.202 AC: 1045 AN: 5178

South Asian (SAS) AF: 0.400 AC: 1932 AN: 4824

European-Finnish (FIN) AF: 0.446 AC: 4716 AN: 10564

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21845 AN: 67956

Other (OTH) AF: 0.276 AC: 584 AN: 2116

Alfa AF: 0.315 Hom.: 36394

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.00058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.085	N
PhyloP100		-1.4
PROVEAN	Benign	0.18	N
REVEL	Benign	0.054
Sift	Benign	0.73	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.098
ClinPred		0.0083	T
GERP RS		-9.4
PromoterAI		-0.022	Neutral
Varity_R		0.022
gMVP		0.25
Mutation Taster		=99/1	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

Other links and lift over

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