16-69165386-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032830.3(UTP4):c.1693C>T(p.Arg565Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,614,032 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 9 hom. )

Consequence

UTP4
NM_032830.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.85

Publications

23 publications found

Variant links:

Genes affected

UTP4 (HGNC:1983): (UTP4 small subunit processome component) This gene encodes a WD40-repeat-containing protein that is localized to the nucleolus. Mutation of this gene causes North American Indian childhood cirrhosis, a severe intrahepatic cholestasis that results in transient neonatal jaundice, and progresses to periportal fibrosis and cirrhosis in childhood and adolescence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

UTP4 Gene-Disease associations (from GenCC):

hereditary North American Indian childhood cirrhosis
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P
cirrhosis, familial
Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

UTP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012974888).

BP6

Variant 16-69165386-C-T is Benign according to our data. Variant chr16-69165386-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3194.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000918 (1342/1461884) while in subpopulation AMR AF = 0.016 (717/44724). AF 95% confidence interval is 0.0151. There are 9 homozygotes in GnomAdExome4. There are 642 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UTP4	NM_032830.3 link	c.1693C>T	p.Arg565Trp	missense_variant	Exon 15 of 17	ENST00000314423.12	NP_116219.2	Q969X6-1
UTP4	NM_001318391.2 link	c.1444C>T	p.Arg482Trp	missense_variant	Exon 15 of 17		NP_001305320.1
UTP4	XM_005256205.4 link	c.1276C>T	p.Arg426Trp	missense_variant	Exon 11 of 13		XP_005256262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UTP4	ENST00000314423.12 link	c.1693C>T	p.Arg565Trp	missense_variant	Exon 15 of 17	1	NM_032830.3	ENSP00000327179.7		Q969X6-1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

235

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00325

AC:

818

AN:

251478

AF XY:

0.00267

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0178

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000918

AC:

1342

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000883

AC XY:

642

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.0160

AC:

717

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

299

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00168

AC:

145

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000872

AC:

AN:

1112006

Other (OTH)

AF:

0.00116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

176

265

353

441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00155

AC:

236

AN:

152148

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

133

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41488

American (AMR)

AF:

0.0108

AC:

165

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68010

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000877

Hom.:

Bravo

AF:

0.00206

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00245

AC:

298

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary North American Indian childhood cirrhosis

Uncertain:1Benign:1

Mar 05, 2015

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Arg565Trp variant in CIRH1A has been identified in 22 relatives from 5 Ojibway-Cree families with North American Indian childhood cirrhosis and in the heterozygous state in 1 Qatari individual (PMID: 12417987, 24123366), but has also been identified in >1% of Latino chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg565Trp variant may not impact protein function (PMID: 16225863). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive North American Indian childhood cirrhosis. -

UTP4-related disorder

Uncertain:1

May 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The UTP4 c.1693C>T variant is predicted to result in the amino acid substitution p.Arg565Trp. This variant has been reported in the homozygous state in at least 34 individuals affected with progressive cholestasis of northwestern Quebec (Chagnon et al. 2002. PubMed ID: 12417987; Khendek et al. 2022. PubMed ID: 36133898). However, this variant is also reported in 1.8% of alleles in individuals of Latino descent in gnomAD, including 7 homozygous individuals. In vitro experimental studies on this variant have been inconclusive (Yu et al. 2005. PubMed ID: 16225863; Yu et al. 2009. PubMed ID: 19732766; Freed et al. 2012. PubMed ID: 22916032). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 565 of the UTP4 protein (p.Arg565Trp). This variant is present in population databases (rs119465999, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with North American Indian childhood cirrhosis (PMID: 12417987). ClinVar contains an entry for this variant (Variation ID: 3194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UTP4 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on UTP4 function (PMID: 16225863, 19732766, 20385600, 22916032). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.42

T;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D;D

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.89

PhyloP100

1.9

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.80

MVP

0.78

MPC

0.76

ClinPred

0.085

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.50

Mutation Taster

=95/5

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over