chr16-69136838-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_032830.3(UTP4):​c.302G>T​(p.Gly101Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,614,160 control chromosomes in the GnomAD database, including 13 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 0.0023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0036 ( 13 hom. )

Consequence

UTP4
NM_032830.3 missense

Scores

7
5
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.03
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02347508).
BP6
Variant 16-69136838-G-T is Benign according to our data. Variant chr16-69136838-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 710240.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
UTP4NM_032830.3 linkuse as main transcriptc.302G>T p.Gly101Val missense_variant 3/17 ENST00000314423.12
UTP4NM_001318391.2 linkuse as main transcriptc.53G>T p.Gly18Val missense_variant 3/17
UTP4XM_047434817.1 linkuse as main transcriptc.302G>T p.Gly101Val missense_variant 3/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UTP4ENST00000314423.12 linkuse as main transcriptc.302G>T p.Gly101Val missense_variant 3/171 NM_032830.3 P1Q969X6-1

Frequencies

GnomAD3 genomes
AF:
0.00227
AC:
346
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000676
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00373
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00348
Gnomad OTH
AF:
0.00574
GnomAD3 exomes
AF:
0.00223
AC:
561
AN:
251488
Hom.:
3
AF XY:
0.00232
AC XY:
316
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.000923
Gnomad AMR exome
AF:
0.00344
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000653
Gnomad FIN exome
AF:
0.000277
Gnomad NFE exome
AF:
0.00326
Gnomad OTH exome
AF:
0.00309
GnomAD4 exome
AF:
0.00362
AC:
5287
AN:
1461848
Hom.:
13
Cov.:
32
AF XY:
0.00357
AC XY:
2594
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00335
Gnomad4 ASJ exome
AF:
0.00142
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000927
Gnomad4 FIN exome
AF:
0.000524
Gnomad4 NFE exome
AF:
0.00428
Gnomad4 OTH exome
AF:
0.00353
GnomAD4 genome
AF:
0.00227
AC:
346
AN:
152312
Hom.:
0
Cov.:
32
AF XY:
0.00228
AC XY:
170
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.000674
Gnomad4 AMR
AF:
0.00373
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.00348
Gnomad4 OTH
AF:
0.00568
Alfa
AF:
0.00309
Hom.:
4
Bravo
AF:
0.00267
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00519
AC:
20
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00453
AC:
39
ExAC
AF:
0.00200
AC:
243
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00267
EpiControl
AF:
0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary North American Indian childhood cirrhosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
UTP4-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 21, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Uncertain
0.024
T
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
28
DANN
Benign
0.97
DEOGEN2
Benign
0.34
.;T;.;.;T;.;.;T;T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.023
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.34
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-7.8
.;D;D;.;.;D;D;D;.
REVEL
Uncertain
0.63
Sift
Uncertain
0.014
.;D;D;.;.;D;D;D;.
Sift4G
Pathogenic
0.0
D;T;D;D;D;T;D;T;D
Polyphen
1.0
.;D;.;.;.;.;D;.;.
Vest4
0.85, 0.87, 0.86
MVP
0.86
MPC
0.83
ClinPred
0.065
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.88
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs144369314; hg19: chr16-69170741; COSMIC: COSV58735169; COSMIC: COSV58735169; API