Genetic Variant RFPL4A:p.Leu15Val (chr19-55761843-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001145014.2(RFPL4A):c.43C>G(p.Leu15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,481,212 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 8 hom., cov: 26)

Exomes 𝑓: 0.0015 ( 117 hom. )

Consequence

RFPL4A
NM_001145014.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.877

Variant links:

Genes affected

RFPL4A (HGNC:16449): (ret finger protein like 4A) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to be located in nucleus. Predicted to be active in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RFPL4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013174981).

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL4A	NM_001145014.2 link	c.43C>G	p.Leu15Val	missense_variant	Exon 2 of 3	ENST00000434937.3	NP_001138486.1	A6NLU0
RFPL4A	XM_011526915.4 link	c.214C>G	p.Leu72Val	missense_variant	Exon 3 of 4		XP_011525217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFPL4A	ENST00000434937.3 link	c.43C>G	p.Leu15Val	missense_variant	Exon 2 of 3	5	NM_001145014.2	ENSP00000392936.2		A6NLU0

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

151

AN:

140326

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000413

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00174

Gnomad ASJ

AF:

0.000297

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00173

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000940

AC:

138

AN:

146758

Hom.:

AF XY:

0.000834

AC XY:

AN XY:

77954

show subpopulations

Gnomad AFR exome

AF:

0.000146

Gnomad AMR exome

AF:

0.000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000564

Gnomad FIN exome

AF:

0.000243

Gnomad NFE exome

AF:

0.00177

Gnomad OTH exome

AF:

0.000483

GnomAD4 exome

AF:

0.00148

AC:

1987

AN:

1340770

Hom.:

117

Cov.:

AF XY:

0.00148

AC XY:

979

AN XY:

662416

show subpopulations

Gnomad4 AFR exome

AF:

0.000137

Gnomad4 AMR exome

AF:

0.000916

Gnomad4 ASJ exome

AF:

0.0000407

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000388

Gnomad4 FIN exome

AF:

0.000350

Gnomad4 NFE exome

AF:

0.00180

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.00108

AC:

151

AN:

140442

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

68704

show subpopulations

Gnomad4 AFR

AF:

0.000412

Gnomad4 AMR

AF:

0.00174

Gnomad4 ASJ

AF:

0.000297

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00173

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000473

Hom.:

ExAC

AF:

0.000700

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.43C>G (p.L15V) alteration is located in exon 2 (coding exon 1) of the RFPL4A gene. This alteration results from a C to G substitution at nucleotide position 43, causing the leucine (L) at amino acid position 15 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.37

DANN

Benign

0.78

DEOGEN2

Benign

0.093

Eigen

Benign

-0.79

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.39

M_CAP

Benign

0.0018

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

REVEL

Benign

0.076

Sift

Benign

0.36

Sift4G

Benign

0.14

Polyphen

0.81

Vest4

0.086

MVP

0.23

MPC

1.0

ClinPred

0.031

GERP RS

-2.6

Varity_R

0.028

gMVP

0.14

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