Variant 1-201999950-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020216.4(RNPEP):c.1139G>A(p.Arg380His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

RNPEP
NM_020216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48

Variant links:

Genes affected

RNPEP (HGNC:10078): (arginyl aminopeptidase) Predicted to enable metalloaminopeptidase activity. Predicted to be involved in proteolysis. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

RNPEP links:

ELF3-AS1 (HGNC:40211): (ELF3 antisense RNA 1)

ELF3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052618742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RNPEP	NM_020216.4 linkuse as main transcript	c.1139G>A	p.Arg380His	missense_variant	6/11	ENST00000295640.9	NP_064601.3
RNPEP	NM_001319182.2 linkuse as main transcript	c.746G>A	p.Arg249His	missense_variant	6/11		NP_001306111.1
RNPEP	NM_001319183.2 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	5/10		NP_001306112.1
RNPEP	NM_001319184.2 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	5/10		NP_001306113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNPEP	ENST00000295640.9 linkuse as main transcript	c.1139G>A	p.Arg380His	missense_variant	6/11	1	NM_020216.4	ENSP00000295640	P1
ELF3-AS1	ENST00000419190.2 linkuse as main transcript	n.1042C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

250904

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000873

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000210

AC:

307

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

145

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000302

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2024

The c.1139G>A (p.R380H) alteration is located in exon 6 (coding exon 6) of the RNPEP gene. This alteration results from a G to A substitution at nucleotide position 1139, causing the arginine (R) at amino acid position 380 to be replaced by a histidine (H). 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

-0.39

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.052

T;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.59

N;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.18

N;N;N

REVEL

Benign

0.081

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.74

T;T;T

Polyphen

0.013

B;.;.

Vest4

0.66

MVP

0.34

MPC

0.22

ClinPred

0.029

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.018

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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