rs2070959

Variant names:

• chr2-233693545-A-G
• rs2070959
• NM_001072.4:c.541A>G
• UGT1A6 p.Thr181Ala

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Moderate

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 cumulative frequency of 0.319 (AC=515,475) in the gnomAD database across 1,613,956 control chromosomes, including 84,631 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.397. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• 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]

UGT1A (HGNC:12529):

ENSG00000224814 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3973 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.300	AC:45649	Hom:7190	AN:151972	Cov:32
GnomAD2 exomes	AF: 0.312	AC:78275	Hom:	AN:251278	Cov:
GnomAD4 exome	AF: 0.321	AC:469827	Hom:77448	AN:1461866	Cov:93
GnomAD4 genome	AF: 0.300	AC:45648	Hom:7183	AN:152090	Cov:32
TOPMed (Bravo)	AF: 0.279	AC:73783	Hom:10705	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.314	AC:240287	Hom:38653	AN:765074	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.292	AC:685	Hom:108	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.222	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.323	AC:97	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.305	AC:3962	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.277	AC:969	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.235	AC:1698	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.327	AC:658	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.245	AC:30128	Hom:3719	AN:122748	Cov:
Turkish Variome	AF: 0.375	AC:2522	Hom:487	AN:6722	Cov:
UK10K	AF: 0.319	AC:2412	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.210	AC:1880	Hom:202	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.313 *	3475	11098	0.315 *	5552	17608
BipEx(Bipolar disorder (including schizoaffective))	0.322	9161	28420	0.316	9104	28844
Epi25(Epilepsy)	0.320	13427	41958	0.307	20551	66888
SCHEMA(Schizophrenia)	0.308	42712	138656	0.315	70273	222822

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.8
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
FuncVEP CTI	Benign	0.0026
GPN-Star LLR	N/A	3.0
GPN-Star score	N/A	-0.76
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.00058	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	99/1	polymorphism (auto)
MutationAssessor	Benign	0.085	N
PhyloP100	Benign	-1.4
popEVE	Benign	-2.7
PromoterAI	N/A	-0.022	Neutral
PROVEAN	Benign	0.18	N
REVEL	Benign	0.054
Sift	Benign	0.73	T
Sift4G	Benign	0.77	T
Varity_R	N/A	0.022
VESM-3B	Benign	-3.6

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2070959;

hg19: chr2-234602191;

COSMIC: COSV59383870;

COSMIC: COSV59383870;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar