Variant 16-15068273-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018427.5(RRN3):c.1449G>C(p.Leu483Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

RRN3
NM_018427.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.814

Variant links:

Genes affected

RRN3 (HGNC:30346): (RRN3 homolog, RNA polymerase I transcription factor) Enables RNA polymerase I core promoter sequence-specific DNA binding activity. Predicted to be involved in transcription initiation from RNA polymerase I promoter. Predicted to act upstream of or within several processes, including DNA-templated transcription, initiation; negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; and regulation of transcription, DNA-templated. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

RRN3 links:

PDXDC1 (HGNC:28995): (pyridoxal dependent decarboxylase domain containing 1) Enables cadherin binding activity. Predicted to be involved in carboxylic acid metabolic process. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

PDXDC1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRN3	NM_018427.5 linkuse as main transcript	c.1449G>C	p.Leu483Phe	missense_variant	15/18	ENST00000198767.11	NP_060897.3	Q9NYV6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRN3	ENST00000198767.11 linkuse as main transcript	c.1449G>C	p.Leu483Phe	missense_variant	15/18	1	NM_018427.5	ENSP00000198767.7		Q9NYV6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000404

AC:

AN:

197816

Hom.:

AF XY:

0.00000919

AC XY:

AN XY:

108816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000327

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000425

AC:

AN:

1410328

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699870

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000174

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000499

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

Jun 05, 2024

The c.1449G>C (p.L483F) alteration is located in exon 15 (coding exon 15) of the RRN3 gene. This alteration results from a G to C substitution at nucleotide position 1449, causing the leucine (L) at amino acid position 483 to be replaced by a phenylalanine (F). 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

Benign

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.4

M;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.12

T;D;T;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

D;.;P;.

Vest4

0.72

MutPred

0.84

Loss of disorder (P = 0.1156);Loss of disorder (P = 0.1156);.;.;

MVP

0.45

MPC

3.6

ClinPred

0.37

GERP RS

0.34

Varity_R

0.063

gMVP

0.48

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