dbSNP rs369449006: UGT2A3:p.Arg475Leu (chr4-68929973-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024743.4(UGT2A3):c.1424G>T(p.Arg475Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R475P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

UGT2A3
NM_024743.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.88

Variant links:

Genes affected

UGT2A3 (HGNC:28528): (UDP glucuronosyltransferase family 2 member A3) Enables glucuronosyltransferase activity. Involved in cellular glucuronidation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

UGT2A3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT2A3	NM_024743.4 link	c.1424G>T	p.Arg475Leu	missense_variant	Exon 6 of 6	ENST00000251566.9	NP_079019.3	Q6UWM9
UGT2A3	XM_011532247.3 link	c.1442G>T	p.Arg481Leu	missense_variant	Exon 6 of 6		XP_011530549.1
UGT2A3	XM_047416177.1 link	c.557G>T	p.Arg186Leu	missense_variant	Exon 6 of 6		XP_047272133.1
UGT2A3	NR_024010.2 link	n.1565G>T		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UGT2A3	ENST00000251566.9 link	c.1424G>T	p.Arg475Leu	missense_variant	Exon 6 of 6	1	NM_024743.4	ENSP00000251566.4	Q6UWM9
UGT2A3	ENST00000503012.1 link	n.*600G>T		non_coding_transcript_exon_variant	Exon 7 of 7	2		ENSP00000424092.1	D6RBL8
UGT2A3	ENST00000503012.1 link	n.*600G>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000424092.1	D6RBL8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250952

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135616

show subpopulations

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

AF:

0.00000274

AC:

AN:

1461442

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.35

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

4.2

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

0.20

Vest4

0.52

MutPred

0.85

Loss of methylation at R475 (P = 0.0176);

MVP

0.60

MPC

0.0086

ClinPred

0.99

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.59

gMVP

0.48

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over