Genetic Variant NM_032334.3:c.389A>G (chr8-116771481-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_032334.3(UTP23):c.389A>G(p.Lys130Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000742 in 1,347,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. K130T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

UTP23
NM_032334.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.66

Variant links:

Genes affected

UTP23 (HGNC:28224): (UTP23 small subunit processome component) Enables mRNA 3'-UTR binding activity and mRNA 5'-UTR binding activity. Predicted to be involved in rRNA processing. Predicted to act upstream of or within endonucleolytic cleavage in 5'-ETS of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to be part of small-subunit processome. Predicted to be active in nucleolus. Implicated in colorectal adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

UTP23 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34831583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UTP23	NM_032334.3 link	c.389A>G	p.Lys130Arg	missense_variant	Exon 3 of 3	ENST00000309822.7	NP_115710.2	Q9BRU9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UTP23	ENST00000309822.7 link	c.389A>G	p.Lys130Arg	missense_variant	Exon 3 of 3	1	NM_032334.3	ENSP00000308332.2		Q9BRU9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.42e-7

AC:

AN:

1347664

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

663086

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28808

American (AMR)

AF:

0.00

AC:

AN:

25226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21508

East Asian (EAS)

AF:

0.00

AC:

AN:

37096

South Asian (SAS)

AF:

0.00

AC:

AN:

65258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5300

European-Non Finnish (NFE)

AF:

9.44e-7

AC:

AN:

1059446

Other (OTH)

AF:

0.00

AC:

AN:

54968

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

Eigen

Benign

0.041

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

M_CAP

Benign

0.012

MetaRNN

Benign

0.35

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.29

PhyloP100

6.7

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.50

REVEL

Benign

0.17

Sift

Benign

0.62

Sift4G

Benign

0.56

Polyphen

0.73

Vest4

0.48

MutPred

0.63

Loss of catalytic residue at K130 (P = 0.0075);

MVP

0.24

MPC

0.24

ClinPred

0.87

GERP RS

6.0

Varity_R

0.078

gMVP

0.35

Mutation Taster

=15/85

disease causing

(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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NM_032334.3:c.389A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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