19-55763152-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001145014.2(RFPL4A):​c.841C>T​(p.Pro281Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,536,188 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000044 ( 2 hom. )

Consequence

RFPL4A
NM_001145014.2 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.249
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]

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=0.08395809).
BP6
Variant 19-55763152-C-T is Benign according to our data. Variant chr19-55763152-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2461246.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RFPL4ANM_001145014.2 linkc.841C>T p.Pro281Ser missense_variant Exon 3 of 3 ENST00000434937.3 NP_001138486.1 A6NLU0
RFPL4AXM_011526915.4 linkc.1012C>T p.Pro338Ser missense_variant Exon 4 of 4 XP_011525217.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RFPL4AENST00000434937.3 linkc.841C>T p.Pro281Ser missense_variant Exon 3 of 3 5 NM_001145014.2 ENSP00000392936.2 A6NLU0

Frequencies

GnomAD3 genomes
AF:
0.0000139
AC:
2
AN:
144110
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000295
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000195
AC:
3
AN:
153794
Hom.:
0
AF XY:
0.0000122
AC XY:
1
AN XY:
81732
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:
0.0000507
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000438
AC:
61
AN:
1392078
Hom.:
2
Cov.:
42
AF XY:
0.0000378
AC XY:
26
AN XY:
686944
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:
0.0000539
Gnomad4 OTH exome
AF:
0.0000520
GnomAD4 genome
AF:
0.0000139
AC:
2
AN:
144110
Hom.:
0
Cov.:
29
AF XY:
0.0000142
AC XY:
1
AN XY:
70482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
ExAC
AF:
0.0000406
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Jan 06, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
1.9
DANN
Benign
0.40
DEOGEN2
Benign
0.023
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.0037
N
LIST_S2
Benign
0.26
T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.084
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.024
Sift
Benign
0.060
T
Sift4G
Benign
0.18
T
Polyphen
0.22
B
Vest4
0.025
MVP
0.076
MPC
0.86
ClinPred
0.034
T
GERP RS
1.5
Varity_R
0.096
gMVP
0.063

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.

Other links and lift over

dbSNP: rs747431754; hg19: chr19-56274518; API