Genetic Variant NM_001098535.1:c.9G>T (chr22-32358080-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001098535.1(RFPL3):c.9G>T(p.Arg3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RFPL3
NM_001098535.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.29

Publications

0 publications found

Variant links:

Genes affected

RFPL3 (HGNC:9980): (ret finger protein like 3) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to be located in cytoplasm. Predicted to be active in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RFPL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05954531).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098535.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFPL3	NM_001098535.1	MANE Select	c.9G>T	p.Arg3Ser	missense	Exon 1 of 2	NP_001092005.1	O75679-1
	RFPL3	NM_006604.2		c.-5-74G>T		intron	N/A	NP_006595.1	O75679-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFPL3	ENST00000249007.4	TSL:1 MANE Select	c.9G>T	p.Arg3Ser	missense	Exon 1 of 2	ENSP00000249007.4	O75679-1
	RFPL3	ENST00000397468.5	TSL:1	c.-5-74G>T		intron	N/A	ENSP00000380609.1	O75679-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726554

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111254

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.092

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.00044

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.39

M_CAP

Benign

0.0019

MetaRNN

Benign

0.060

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-1.3

PROVEAN

Benign

-0.50

REVEL

Benign

0.023

Sift

Benign

0.25

Sift4G

Benign

0.36

Polyphen

0.35

Vest4

0.18

MutPred

0.28

Loss of MoRF binding (P = 9e-04)

MVP

0.15

MPC

0.21

ClinPred

0.067

GERP RS

-0.29

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.080

gMVP

0.25

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over