Genetic Variant UGT2A1:p.Tyr192* (chr4-69647069-A-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

The NM_001252275.3(UGT2A1):c.576T>A(p.Tyr192*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,612,932 control chromosomes in the GnomAD database, including 1,241 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.029 ( 98 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1143 hom. )

Consequence

UGT2A1
NM_001252275.3 stop_gained

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.234

Variant links:

Genes affected

UGT2A1 (HGNC:12542): (UDP glucuronosyltransferase family 2 member A1 complex locus) The protein encoded by this gene belongs to the UDP-glycosyltransferase family. Members of this protein family play a role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. The encoded enzyme is expressed in the olfactory neuroepithelium, which lines the posterior nasal cavity and is exposed to a wide range of odorants and airborne toxic compounds. Hence, this protein has been suggested to be involved in clearing lipophilic odorant molecules from the sensory epithelium. This gene shares exon structure with the UDP glucuronosyltransferase 2A2 family member, which encodes N-terminally distinct isoforms. Polymorphisms in this gene may be associated with the loss of taste and smell that is reported by some individuals during SARS-CoV-2 infection. [provided by RefSeq, Jan 2022]

UGT2A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.029 (4411/151978) while in subpopulation NFE AF= 0.0411 (2786/67854). AF 95% confidence interval is 0.0398. There are 98 homozygotes in gnomad4. There are 2126 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 98 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT2A1	NM_001252275.3 link	c.576T>A	p.Tyr192*	stop_gained	Exon 2 of 7	ENST00000286604.9	NP_001239204.2	P0DTE4-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT2A1	ENST00000286604.9 link	c.576T>A	p.Tyr192*	stop_gained	Exon 2 of 7	1	NM_001252275.3	ENSP00000286604.4		P0DTE4-5

Frequencies

GnomAD3 genomes

AF:

0.0291

AC:

4413

AN:

151860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00807

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.0687

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0329

Gnomad MID

AF:

0.0669

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.0330

GnomAD3 exomes

AF:

0.0327

AC:

8194

AN:

250610

Hom.:

193

AF XY:

0.0332

AC XY:

4501

AN XY:

135444

show subpopulations

Gnomad AFR exome

AF:

0.00659

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0649

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.0358

Gnomad NFE exome

AF:

0.0455

Gnomad OTH exome

AF:

0.0458

GnomAD4 exome

AF:

0.0366

AC:

53410

AN:

1460954

Hom.:

1143

Cov.:

AF XY:

0.0362

AC XY:

26322

AN XY:

726760

show subpopulations

Gnomad4 AFR exome

AF:

0.00709

Gnomad4 AMR exome

AF:

0.0257

Gnomad4 ASJ exome

AF:

0.0661

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0134

Gnomad4 FIN exome

AF:

0.0339

Gnomad4 NFE exome

AF:

0.0404

Gnomad4 OTH exome

AF:

0.0364

GnomAD4 genome

AF:

0.0290

AC:

4411

AN:

151978

Hom.:

Cov.:

AF XY:

0.0286

AC XY:

2126

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00804

Gnomad4 AMR

AF:

0.0348

Gnomad4 ASJ

AF:

0.0687

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.0329

Gnomad4 NFE

AF:

0.0411

Gnomad4 OTH

AF:

0.0327

Alfa

AF:

0.0375

Hom.:

112

Bravo

AF:

0.0290

TwinsUK

AF:

0.0334

AC:

124

ALSPAC

AF:

0.0418

AC:

161

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0413

AC:

355

ExAC

AF:

0.0328

AC:

3978

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0486

EpiControl

AF:

0.0469

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency. Insufficient evidence for gene-disease association. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.11

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.77

Vest4

0.31

GERP RS

-0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over