rs1105879

Variant names:

• chr2-233693556-A-C
• rs1105879
• NM_001072.4:c.552A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-233693556-A-C
• chr2-233693556-A-G
• chr2-233693556-A-T

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.552A>C​(p.Arg184Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,924 control chromosomes in the GnomAD database, including 98,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (8872 hom., cov: 32)
  • Exomes 𝑓: 0.35 (89689 hom.)
• Consequence: UGT1A6 NM_001072.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.880
• Publications: 140 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=2.759695E-4).
• BP6: Variant 2-233693556-A-C is Benign according to our data. Variant chr2-233693556-A-C is described in ClinVar as Benign. ClinVar VariationId is 440380.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A6	NM_001072.4	c.552A>C	p.Arg184Ser	missense_variant	Exon 1 of 5	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.855+56179A>C		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-73478A>C		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+10764A>C		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+20767A>C		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A6	ENST00000305139.11	c.552A>C	p.Arg184Ser	missense_variant	Exon 1 of 5	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.855+56179A>C		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+20767A>C		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.855+10764A>C		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-73478A>C		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51227 AN: 151946 Hom.: 8872 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.317

GnomAD2 exomes AF: 0.345 AC: 86690 AN: 251270 AF XY: 0.355

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.346 AC: 506448 AN: 1461862 Hom.: 89689 Cov.: 97 AF XY: 0.351 AC XY: 255193 AN XY: 727228

African (AFR) AF: 0.306 AC: 10252 AN: 33480

American (AMR) AF: 0.232 AC: 10394 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 11090 AN: 26132

East Asian (EAS) AF: 0.240 AC: 9505 AN: 39686

South Asian (SAS) AF: 0.443 AC: 38196 AN: 86256

European-Finnish (FIN) AF: 0.462 AC: 24701 AN: 53418

Middle Eastern (MID) AF: 0.368 AC: 2123 AN: 5768

European-Non Finnish (NFE) AF: 0.341 AC: 379350 AN: 1112004

Other (OTH) AF: 0.345 AC: 20837 AN: 60394

GnomAD4 genome AF: 0.337 AC: 51241 AN: 152062 Hom.: 8872 Cov.: 32 AF XY: 0.345 AC XY: 25637 AN XY: 74336

African (AFR) AF: 0.299 AC: 12411 AN: 41472

American (AMR) AF: 0.290 AC: 4438 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1469 AN: 3468

East Asian (EAS) AF: 0.231 AC: 1197 AN: 5176

South Asian (SAS) AF: 0.443 AC: 2137 AN: 4826

European-Finnish (FIN) AF: 0.488 AC: 5153 AN: 10552

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23216 AN: 67948

Other (OTH) AF: 0.315 AC: 667 AN: 2116

Alfa AF: 0.342 Hom.: 42478

Bravo AF: 0.318

TwinsUK AF: 0.330 AC: 1223

ALSPAC AF: 0.348 AC: 1342

ESP6500AA AF: 0.305 AC: 1345

ESP6500EA AF: 0.358 AC: 3076

ExAC AF: 0.346 AC: 41958

Asia WGS AF: 0.322 AC: 1125 AN: 3478

EpiCase AF: 0.356

EpiControl AF: 0.354

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.051	T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.00028	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	.;L
PhyloP100		-0.88
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.023
Sift	Benign	0.034	D;T
Sift4G	Uncertain	0.026	D;T
Polyphen		0.038	.;B
Vest4		0.058
MutPred		0.22		Gain of glycosylation at R184 (P = 0.0327);Gain of glycosylation at R184 (P = 0.0327);
MPC		0.13
ClinPred		0.0056	T
GERP RS		-3.3
PromoterAI		0.0086	Neutral
Varity_R		0.083
gMVP		0.31
Mutation Taster		=94/6	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: rs1105879; hg19: chr2-234602202; COSMIC: COSV59388821; COSMIC: COSV59388821;