rs11692021

chr2-233682559-T-Cchr2-233682559-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019077.3(UGT1A7):c.622T>C(p.Trp208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,613,636 control chromosomes in the GnomAD database, including 115,745 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 0.34 (9225 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106520 hom.)
• Consequence: UGT1A7 NM_019077.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.39

Genes affected

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]

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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.3541193E-4).
• BP6: Variant 2-233682559-T-C is Benign according to our data. Variant chr2-233682559-T-C is described in ClinVar as [Benign]. Clinvar id is 440389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A7	NM_019077.3	c.622T>C	p.Trp208Arg	missense_variant	1/5	ENST00000373426.4
UGT1A10	NM_019075.4	c.855+45182T>C		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.855+63997T>C		intron_variant		ENST00000373450.5
UGT1A9	NM_021027.3	c.855+9770T>C		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A7	ENST00000373426.4	c.622T>C	p.Trp208Arg	missense_variant	1/5	1	NM_019077.3	P1
UGT1A10	ENST00000344644.10	c.855+45182T>C		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+9770T>C		intron_variant		1	NM_021027.3	P1
UGT1A8	ENST00000373450.5	c.855+63997T>C		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51784 AN: 151876 Hom.: 9233 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.318

GnomAD3 exomes AF: 0.349 AC: 87695 AN: 251062 Hom.: 16437 AF XY: 0.360 AC XY: 48803 AN XY: 135674

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.411

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.378 AC: 551905 AN: 1461642 Hom.: 106520 Cov.: 146 AF XY: 0.380 AC XY: 276479 AN XY: 727124

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.441

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.411

Gnomad4 FIN exome AF: 0.451

Gnomad4 NFE exome AF: 0.386

Gnomad4 OTH exome AF: 0.367

GnomAD4 genome AF: 0.341 AC: 51780 AN: 151994 Hom.: 9225 Cov.: 32 AF XY: 0.344 AC XY: 25559 AN XY: 74282

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.440

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.315

Alfa AF: 0.350 Hom.: 4528

Bravo AF: 0.320

TwinsUK AF: 0.378 AC: 1403

ALSPAC AF: 0.398 AC: 1532

ESP6500AA AF: 0.275 AC: 1211

ESP6500EA AF: 0.387 AC: 3331

ExAC AF: 0.351 AC: 42645

EpiCase AF: 0.392

EpiControl AF: 0.391

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 19318555, 11677206, 12122597, 11037804) -
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	0.20
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.015
Dann	Benign	0.52
DEOGEN2	Benign	0.14	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.00035	T
MetaRNN	Benign	0.00044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.38	N
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Benign	2.7	N
REVEL	Benign	0.10
Sift	Benign	0.15	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.022
MutPred		0.20		Gain of helix (P = 0.0128);
MPC		0.19
ClinPred		0.011	T
GERP RS		-8.3
Varity_R		0.058
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11692021; hg19: chr2-234591205; COSMIC: COSV60831418;