2-233618537-G-A

Position:

• chr2-233618537-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_019076.5(UGT1A8):​c.830G>A​(p.Cys277Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0211 in 1,613,720 control chromosomes in the GnomAD database, including 504 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.022 (482 hom.)
• Consequence: UGT1A8 NM_019076.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.37

Genes affected

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071814954).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2010/152216) while in subpopulation NFE AF= 0.0219 (1486/68008). AF 95% confidence interval is 0.0209. There are 22 homozygotes in gnomad4. There are 873 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A8	NM_019076.5	c.830G>A	p.Cys277Tyr	missense_variant	1/5	ENST00000373450.5	NP_061949.3
UGT1A		n.233618537G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A8	ENST00000373450.5	c.830G>A	p.Cys277Tyr	missense_variant	1/5	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2012 AN: 152098 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0123 AC: 3092 AN: 250656 Hom.: 34 AF XY: 0.0120 AC XY: 1622 AN XY: 135498

Gnomad AFR exome AF: 0.00527

Gnomad AMR exome AF: 0.00827

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0219 AC: 32074 AN: 1461504 Hom.: 482 Cov.: 33 AF XY: 0.0210 AC XY: 15289 AN XY: 727020

Gnomad4 AFR exome AF: 0.00403

Gnomad4 AMR exome AF: 0.00962

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00457

Gnomad4 NFE exome AF: 0.0270

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0132 AC: 2010 AN: 152216 Hom.: 22 Cov.: 32 AF XY: 0.0117 AC XY: 873 AN XY: 74434

Gnomad4 AFR AF: 0.00600

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0146 Hom.: 12

Bravo AF: 0.0142

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0222 AC: 191

ExAC AF: 0.0123 AC: 1488

EpiCase AF: 0.0203

EpiControl AF: 0.0229

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.7	H
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.33
ClinPred		0.077	T
GERP RS		4.0
Varity_R		0.91
gMVP		0.47

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: rs17863762; hg19: chr2-234527183;