dbSNP rs17863762: UGT1A8:p.Cys277Tyr (chr2-233618537-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C277S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 22 hom., cov: 32)

Exomes 𝑓: 0.022 ( 482 hom. )

Consequence

UGT1A8
NM_019076.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.37

Publications

25 publications found

Variant links:

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]

UGT1A8 links:

UGT1A (HGNC:12529):

UGT1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A8	NM_019076.5 link	c.830G>A	p.Cys277Tyr	missense_variant	Exon 1 of 5	ENST00000373450.5	NP_061949.3
UGT1A		n.233618537G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A8	ENST00000373450.5 link	c.830G>A	p.Cys277Tyr	missense_variant	Exon 1 of 5	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2012

AN:

152098

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0123

AC:

3092

AN:

250656

AF XY:

0.0120

show subpopulations

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 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.:

AF XY:

0.0210

AC XY:

15289

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00403

AC:

135

AN:

33470

American (AMR)

AF:

0.00962

AC:

430

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39696

South Asian (SAS)

AF:

0.00116

AC:

100

AN:

86236

European-Finnish (FIN)

AF:

0.00457

AC:

244

AN:

53416

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0270

AC:

30012

AN:

1111710

Other (OTH)

AF:

0.0177

AC:

1070

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

2043

4086

6129

8172

10215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1158

2316

3474

4632

5790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0132

AC:

2010

AN:

152216

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

873

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00600

AC:

249

AN:

41534

American (AMR)

AF:

0.0118

AC:

180

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00289

AC:

AN:

3466

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00187

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00397

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0219

AC:

1486

AN:

68008

Other (OTH)

AF:

0.0109

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00521

Hom.:

Bravo

AF:

0.0142

TwinsUK

AF:

0.0278

AC:

103

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00499

AC:

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

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0072

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.7

PhyloP100

6.4

PROVEAN

Pathogenic

-10

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.33

ClinPred

0.077

GERP RS

4.0

Varity_R

0.91

gMVP

0.47

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over