Genetic Variant RFPL4A:p.Ala131Val (chr19-55762703-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001145014.2(RFPL4A):c.392C>T(p.Ala131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000461 in 151,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 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: 0.749

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13746756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL4A	NM_001145014.2 link	c.392C>T	p.Ala131Val	missense_variant	Exon 3 of 3	ENST00000434937.3	NP_001138486.1	A6NLU0
RFPL4A	XM_011526915.4 link	c.563C>T	p.Ala188Val	missense_variant	Exon 4 of 4		XP_011525217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFPL4A	ENST00000434937.3 link	c.392C>T	p.Ala131Val	missense_variant	Exon 3 of 3	5	NM_001145014.2	ENSP00000392936.2		A6NLU0

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000885

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000192

AC:

AN:

156026

Hom.:

AF XY:

0.0000242

AC XY:

AN XY:

82734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000499

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000193

AC:

AN:

1399202

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

690120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000241

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151770

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74100

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000885

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.392C>T (p.A131V) alteration is located in exon 3 (coding exon 2) of the RFPL4A gene. This alteration results from a C to T substitution at nucleotide position 392, causing the alanine (A) at amino acid position 131 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

0.15

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.8

DANN

Uncertain

0.98

DEOGEN2

Benign

0.046

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.64

M_CAP

Benign

0.0013

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.10

Sift

Benign

0.078

Sift4G

Benign

0.15

Polyphen

0.68

Vest4

0.14

MutPred

0.46

Loss of ubiquitination at K128 (P = 0.0779);

MVP

0.048

MPC

0.86

ClinPred

0.085

GERP RS

-0.76

Varity_R

0.060

gMVP

0.070

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