16-69165386-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 3194.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome 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 gnomad4_exome. There are 642 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UTP4	NM_032830.3	c.1693C>T	p.Arg565Trp	missense_variant	15/17	ENST00000314423.12
UTP4	NM_001318391.2	c.1444C>T	p.Arg482Trp	missense_variant	15/17
UTP4	XM_005256205.4	c.1276C>T	p.Arg426Trp	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UTP4	ENST00000314423.12	c.1693C>T	p.Arg565Trp	missense_variant	15/17	1	NM_032830.3	P1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 235 AN: 152030 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00325 AC: 818 AN: 251478 Hom.: 7 AF XY: 0.00267 AC XY: 363 AN XY: 135916

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 SAS exome AF: 0.00180

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.: 9 Cov.: 31 AF XY: 0.000883 AC XY: 642 AN XY: 727248

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152148 Hom.: 2 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74386

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000961 Hom.: 1

Bravo AF: 0.00206

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00245 AC: 298

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary North American Indian childhood cirrhosis Uncertain:1 Benign:1

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Mar 05, 2015	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.025	A;A;A
PrimateAI	Uncertain	0.56	T
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	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.50

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

Other links and lift over

dbSNP: rs119465999; hg19: chr16-69199289;