2-233693023-T-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.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. 13/19 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 0.39 (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

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• 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/exons	MANE	UniProt
UGT1A6	NM_001072.4	c.19T>G	p.Ser7Ala	missense_variant	1/5	ENST00000305139.11
UGT1A10	NM_019075.4	c.855+55646T>G		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.856-74011T>G		intron_variant		ENST00000373450.5
UGT1A7	NM_019077.3	c.855+10231T>G		intron_variant		ENST00000373426.4
UGT1A9	NM_021027.3	c.855+20234T>G		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A6	ENST00000305139.11	c.19T>G	p.Ser7Ala	missense_variant	1/5	1	NM_001072.4	P1
UGT1A10	ENST00000344644.10	c.855+55646T>G		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+20234T>G		intron_variant		1	NM_021027.3	P1
UGT1A7	ENST00000373426.4	c.855+10231T>G		intron_variant		1	NM_019077.3	P1
UGT1A8	ENST00000373450.5	c.856-74011T>G		intron_variant		1	NM_019076.5	P1

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

GnomAD3 exomes AF: 0.386 AC: 96845 AN: 250596 Hom.: 19637 AF XY: 0.395 AC XY: 53546 AN XY: 135626

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 SAS exome AF: 0.454

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

Gnomad4 AFR exome AF: 0.379

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.463

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.490

Gnomad4 NFE exome AF: 0.407

Gnomad4 OTH exome AF: 0.400

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

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.465

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.517

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.369

Alfa AF: 0.401 Hom.: 29589

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

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	0.071
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
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
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
Varity_R		0.024
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs6759892; hg19: chr2-234601669; COSMIC: COSV59388807; COSMIC: COSV59388807;