Genetic Variant RFPL4A:p.Ala69Val (chr19-55762006-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001145014.2(RFPL4A):c.206C>T(p.Ala69Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 146,446 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00027 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RFPL4A
NM_001145014.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.10

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016938537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL4A	NM_001145014.2 link	c.206C>T	p.Ala69Val	missense_variant	Exon 2 of 3	ENST00000434937.3	NP_001138486.1	A6NLU0
RFPL4A	XM_011526915.4 link	c.377C>T	p.Ala126Val	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.206C>T	p.Ala69Val	missense_variant	Exon 2 of 3	5	NM_001145014.2	ENSP00000392936.2		A6NLU0

Frequencies

GnomAD3 genomes

AF:

0.000273

AC:

AN:

146336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000470

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000676

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000216

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000271

Gnomad OTH

AF:

0.000993

GnomAD3 exomes

AF:

0.000212

AC:

AN:

150640

Hom.:

AF XY:

0.000225

AC XY:

AN XY:

79946

show subpopulations

Gnomad AFR exome

AF:

0.000688

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000894

Gnomad SAS exome

AF:

0.000232

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000363

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000195

AC:

266

AN:

1363472

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

135

AN XY:

672694

show subpopulations

Gnomad4 AFR exome

AF:

0.000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000558

Gnomad4 SAS exome

AF:

0.000154

Gnomad4 FIN exome

AF:

0.0000204

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.000194

GnomAD4 genome

AF:

0.000273

AC:

AN:

146446

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

AN XY:

71516

show subpopulations

Gnomad4 AFR

AF:

0.000468

Gnomad4 AMR

AF:

0.0000675

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000216

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000271

Gnomad4 OTH

AF:

0.000982

Alfa

AF:

0.000158

Hom.:

ExAC

AF:

0.000175

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.206C>T (p.A69V) alteration is located in exon 2 (coding exon 1) of the RFPL4A gene. This alteration results from a C to T substitution at nucleotide position 206, causing the alanine (A) at amino acid position 69 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

0.13

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.7

DANN

Benign

0.70

DEOGEN2

Benign

0.021

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.26

M_CAP

Benign

0.0017

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

REVEL

Benign

0.014

Sift

Benign

0.32

Sift4G

Benign

0.30

Polyphen

0.33

Vest4

0.028

MVP

0.014

MPC

0.82

ClinPred

0.0053

GERP RS

-6.6

Varity_R

0.034

gMVP

0.061

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