rs750560276

Variant names:

• chr2-233672446-G-A
• rs750560276
• NM_021027.3:c.512G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-233672446-G-A
• chr2-233672446-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021027.3(UGT1A9):​c.512G>A​(p.Gly171Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UGT1A9 NM_021027.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11

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]

UGT1A (HGNC:12529):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A9	NM_021027.3	c.512G>A	p.Gly171Glu	missense_variant	Exon 1 of 5	ENST00000354728.5	NP_066307.1
UGT1A10	NM_019075.4	c.855+35069G>A		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.855+53884G>A		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A		n.233672446G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A9	ENST00000354728.5	c.512G>A	p.Gly171Glu	missense_variant	Exon 1 of 5	1	NM_021027.3	ENSP00000346768.4
UGT1A10	ENST00000344644.10	c.855+35069G>A		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A8	ENST00000373450.5	c.855+53884G>A		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4
UGT1A10	ENST00000373445.1	c.855+35069G>A		intron_variant	Intron 1 of 4	1		ENSP00000362544.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251014 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0068	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.8	M
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.29
Sift	Benign	0.21	T
Sift4G	Benign	0.13	T
Polyphen		0.92	P
Vest4		0.73
MutPred		0.62		Gain of catalytic residue at G171 (P = 0.0513);
MVP		0.55
MPC		0.12
ClinPred		0.75	D
GERP RS		2.5
Varity_R		0.26
gMVP		0.54

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: rs750560276; hg19: chr2-234581092; COSMIC: COSV60841085;