2-233682354-G-C

Position:

• chr2-233682354-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_019077.3(UGT1A7):​c.417G>C​(p.Glu139Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,614,052 control chromosomes in the GnomAD database, including 33 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0086 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (15 hom.)
• Consequence: UGT1A7 NM_019077.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.393

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033971071).
• BP6: Variant 2-233682354-G-C is Benign according to our data. Variant chr2-233682354-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1330505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00855 (1302/152244) while in subpopulation AFR AF= 0.0292 (1212/41534). AF 95% confidence interval is 0.0278. There are 18 homozygotes in gnomad4. There are 602 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A7	NM_019077.3	c.417G>C	p.Glu139Asp	missense_variant	1/5	ENST00000373426.4	NP_061950.2
UGT1A10	NM_019075.4	c.855+44977G>C		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.855+63792G>C		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A9	NM_021027.3	c.855+9565G>C		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A7	ENST00000373426.4	c.417G>C	p.Glu139Asp	missense_variant	1/5	1	NM_019077.3	ENSP00000362525	P1
UGT1A10	ENST00000344644.10	c.855+44977G>C		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.855+9565G>C		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A8	ENST00000373450.5	c.855+63792G>C		intron_variant		1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1299 AN: 152126 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00274 AC: 689 AN: 251112 Hom.: 4 AF XY: 0.00225 AC XY: 306 AN XY: 135700

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00136 AC: 1983 AN: 1461808 Hom.: 15 Cov.: 146 AF XY: 0.00124 AC XY: 905 AN XY: 727208

Gnomad4 AFR exome AF: 0.0320

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000531

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00855 AC: 1302 AN: 152244 Hom.: 18 Cov.: 32 AF XY: 0.00809 AC XY: 602 AN XY: 74450

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00164 Hom.: 2

Bravo AF: 0.00940

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.99	D;D;N;D;D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.0080
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.044	B
Vest4		0.18
MutPred		0.41		Gain of ubiquitination at K138 (P = 0.2249);
MVP		0.18
MPC		0.10
ClinPred		0.0021	T
GERP RS		0.61
Varity_R		0.096
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs114052958; hg19: chr2-234591000;