Genetic Variant RFPL4A:p.Thr143Asn (chr19-55762739-C-A) – 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.428C>A(p.Thr143Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.000033 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000074 ( 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: -1.30

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=0.040818453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL4A	NM_001145014.2 link	c.428C>A	p.Thr143Asn	missense_variant	Exon 3 of 3	ENST00000434937.3	NP_001138486.1	A6NLU0
RFPL4A	XM_011526915.4 link	c.599C>A	p.Thr200Asn	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.428C>A	p.Thr143Asn	missense_variant	Exon 3 of 3	5	NM_001145014.2	ENSP00000392936.2		A6NLU0

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150762

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000743

AC:

104

AN:

1399066

Hom.:

Cov.:

AF XY:

0.0000768

AC XY:

AN XY:

690040

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00143

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000366

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000232

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000331

AC:

AN:

150882

Hom.:

Cov.:

AF XY:

0.0000678

AC XY:

AN XY:

73730

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000423

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000434

Hom.:

ExAC

AF:

0.000226

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428C>A (p.T143N) alteration is located in exon 3 (coding exon 2) of the RFPL4A gene. This alteration results from a C to A substitution at nucleotide position 428, causing the threonine (T) at amino acid position 143 to be replaced by an asparagine (N). 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

-0.51

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.020

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.22

M_CAP

Benign

0.0021

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

REVEL

Benign

0.013

Sift

Uncertain

0.011

Sift4G

Uncertain

0.015

Polyphen

0.086

Vest4

0.087

MutPred

0.42

Loss of phosphorylation at T143 (P = 0.0418);

MVP

0.030

MPC

1.0

ClinPred

0.026

GERP RS

1.6

Varity_R

0.17

gMVP

0.067

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