NM_001072.4:c.19T>G

Variant names:

• chr2-233693023-T-G
• rs6759892
• NM_001072.4:c.19T>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.19T>G​(p.Ser7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,613,808 control chromosomes in the GnomAD database, including 133,167 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (11943 hom., cov: 31)
  • Exomes 𝑓: 0.40 (121224 hom.)
• Consequence: UGT1A6 NM_001072.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.105
• Publications: 127 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):

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=2.0334125E-4).
• BP6: Variant 2-233693023-T-G is Benign according to our data. Variant chr2-233693023-T-G is described in ClinVar as [Benign]. Clinvar id is 440378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A6	NM_001072.4	c.19T>G	p.Ser7Ala	missense_variant	Exon 1 of 5	ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.855+55646T>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-74011T>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+10231T>G		intron_variant	Intron 1 of 4	ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+20234T>G		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.19T>G	p.Ser7Ala	missense_variant	Exon 1 of 5	1	NM_001072.4	ENSP00000303174.6
UGT1A10	ENST00000344644.10	c.855+55646T>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+20234T>G		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A7	ENST00000373426.4	c.855+10231T>G		intron_variant	Intron 1 of 4	1	NM_019077.3	ENSP00000362525.3
UGT1A8	ENST00000373450.5	c.856-74011T>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59777 AN: 151892 Hom.: 11944 Cov.: 31

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.372

GnomAD2 exomes AF: 0.386 AC: 96845 AN: 250596 AF XY: 0.395

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.406

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.404 AC: 590417 AN: 1461796 Hom.: 121224 Cov.: 71 AF XY: 0.407 AC XY: 295643 AN XY: 727182

African (AFR) AF: 0.379 AC: 12681 AN: 33474

American (AMR) AF: 0.264 AC: 11803 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 12104 AN: 26130

East Asian (EAS) AF: 0.240 AC: 9517 AN: 39690

South Asian (SAS) AF: 0.454 AC: 39130 AN: 86224

European-Finnish (FIN) AF: 0.490 AC: 26181 AN: 53414

Middle Eastern (MID) AF: 0.422 AC: 2435 AN: 5764

European-Non Finnish (NFE) AF: 0.407 AC: 452389 AN: 1111994

Other (OTH) AF: 0.400 AC: 24177 AN: 60392

GnomAD4 genome AF: 0.393 AC: 59796 AN: 152012 Hom.: 11943 Cov.: 31 AF XY: 0.398 AC XY: 29572 AN XY: 74298

African (AFR) AF: 0.376 AC: 15580 AN: 41450

American (AMR) AF: 0.338 AC: 5167 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1615 AN: 3472

East Asian (EAS) AF: 0.230 AC: 1190 AN: 5174

South Asian (SAS) AF: 0.455 AC: 2185 AN: 4806

European-Finnish (FIN) AF: 0.517 AC: 5457 AN: 10546

Middle Eastern (MID) AF: 0.393 AC: 114 AN: 290

European-Non Finnish (NFE) AF: 0.401 AC: 27255 AN: 67966

Other (OTH) AF: 0.369 AC: 777 AN: 2108

Alfa AF: 0.399 Hom.: 53275

Bravo AF: 0.377

TwinsUK AF: 0.399 AC: 1479

ALSPAC AF: 0.416 AC: 1603

ESP6500AA AF: 0.386 AC: 1700

ESP6500EA AF: 0.414 AC: 3557

ExAC AF: 0.389 AC: 47194

Asia WGS AF: 0.335 AC: 1171 AN: 3478

EpiCase AF: 0.412

EpiControl AF: 0.414

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	0.071
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.87
DANN	Benign	0.60
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.064	T;T
MetaRNN	Benign	0.00020	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.59	.;N
PhyloP100		-0.10
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.069
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.016
MPC		0.082
ClinPred		0.00055	T
GERP RS		-0.72
PromoterAI		0.0046	Neutral
Varity_R		0.024
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6759892; hg19: chr2-234601669; COSMIC: COSV59388807; COSMIC: COSV59388807;