Variant 4-69480792-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_021139.3(UGT2B4):c.1429C>T(p.Arg477Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,944 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

UGT2B4
NM_021139.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.738

Variant links:

Genes affected

UGT2B4 (HGNC:12553): (UDP glucuronosyltransferase family 2 member B4) Enables glucuronosyltransferase activity. Involved in cellular glucuronidation and estrogen metabolic process. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

UGT2B4 links:

Genome browser will be placed here

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, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UGT2B4	NM_021139.3 linkuse as main transcript	c.1429C>T	p.Arg477Trp	missense_variant	6/6	ENST00000305107.7
UGT2B4	NM_001297616.2 linkuse as main transcript	c.1021C>T	p.Arg341Trp	missense_variant	7/7
UGT2B4	NM_001297615.2 linkuse as main transcript	c.*99C>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT2B4	ENST00000305107.7 linkuse as main transcript	c.1429C>T	p.Arg477Trp	missense_variant	6/6	1	NM_021139.3	P1	P06133-1
UGT2B4	ENST00000512583.5 linkuse as main transcript	c.*99C>T		3_prime_UTR_variant	5/5	1			P06133-3
UGT2B4	ENST00000506580.5 linkuse as main transcript	n.991C>T		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251260

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.1429C>T (p.R477W) alteration is located in exon 6 (coding exon 6) of the UGT2B4 gene. This alteration results from a C to T substitution at nucleotide position 1429, causing the arginine (R) at amino acid position 477 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.048

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

4.3

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-7.3

REVEL

Uncertain

0.45

Sift

Uncertain

0.018

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.55

MutPred

0.91

Loss of disorder (P = 0.0084);

MVP

0.32

MPC

0.041

ClinPred

0.68

GERP RS

-1.3

Varity_R

0.47

gMVP

0.41

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