chr2-233672434-T-C

Position:

• chr2-233672434-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_021027.3(UGT1A9):​c.500T>C​(p.Val167Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,613,976 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (3 hom.)
• Consequence: UGT1A9 NM_021027.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.52

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016549855).
• BP6: Variant 2-233672434-T-C is Benign according to our data. Variant chr2-233672434-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3046264.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A9	NM_021027.3	c.500T>C	p.Val167Ala	missense_variant	1/5	ENST00000354728.5	NP_066307.1
UGT1A10	NM_019075.4	c.855+35057T>C		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.855+53872T>C		intron_variant		ENST00000373450.5	NP_061949.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A9	ENST00000354728.5	c.500T>C	p.Val167Ala	missense_variant	1/5	1	NM_021027.3	ENSP00000346768	P1
UGT1A10	ENST00000344644.10	c.855+35057T>C		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A8	ENST00000373450.5	c.855+53872T>C		intron_variant		1	NM_019076.5	ENSP00000362549	P1
UGT1A10	ENST00000373445.1	c.855+35057T>C		intron_variant		1		ENSP00000362544

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000920 AC: 231 AN: 251094 Hom.: 1 AF XY: 0.000980 AC XY: 133 AN XY: 135690

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.000917 AC: 1340 AN: 1461670 Hom.: 3 Cov.: 33 AF XY: 0.000895 AC XY: 651 AN XY: 727144

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74468

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000340 Hom.: 0

Bravo AF: 0.00134

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00105 AC: 128

EpiCase AF: 0.00175

EpiControl AF: 0.00154

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

UGT1A9-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Uncertain	0.014	D
Sift4G	Benign	0.087	T
Polyphen		0.35	B
Vest4		0.18
MVP		0.20
MPC		0.082
ClinPred		0.016	T
GERP RS		3.4
Varity_R		0.19
gMVP		0.23

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: rs151238339; hg19: chr2-234581080;