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GeneBe

2-240573117-C-T

Variant summary

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

The NM_018226.6(RNPEPL1):c.677C>T(p.Ser226Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,605,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

RNPEPL1
NM_018226.6 missense

Scores

8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.552
Variant links:
Genes affected
RNPEPL1 (HGNC:10079): (arginyl aminopeptidase like 1) Enables metalloaminopeptidase activity. Involved in proteolysis. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.019972056).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RNPEPL1NM_018226.6 linkuse as main transcriptc.677C>T p.Ser226Leu missense_variant 3/11 ENST00000270357.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNPEPL1ENST00000270357.10 linkuse as main transcriptc.677C>T p.Ser226Leu missense_variant 3/111 NM_018226.6 P1
RNPEPL1ENST00000451363.5 linkuse as main transcriptc.-56-1398C>T intron_variant 4
RNPEPL1ENST00000486058.5 linkuse as main transcriptn.403C>T non_coding_transcript_exon_variant 3/92

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000171
AC:
26
AN:
152170
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.000620
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000159
AC:
38
AN:
238256
Hom.:
0
AF XY:
0.000186
AC XY:
24
AN XY:
129298
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000298
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000280
Gnomad SAS exome
AF:
0.000789
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000841
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000156
AC:
226
AN:
1453034
Hom.:
0
Cov.:
33
AF XY:
0.000190
AC XY:
137
AN XY:
721886
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.0000227
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000557
Gnomad4 SAS exome
AF:
0.00108
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000912
Gnomad4 OTH exome
AF:
0.000150
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000171
AC:
26
AN:
152288
Hom.:
0
Cov.:
34
AF XY:
0.000148
AC XY:
11
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000580
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.000132
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000149
AC:
18
Asia WGS
AF:
0.00202
AC:
7
AN:
3478

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 submitterclinical testingAmbry GeneticsOct 06, 2021The c.677C>T (p.S226L) alteration is located in exon 3 (coding exon 3) of the RNPEPL1 gene. This alteration results from a C to T substitution at nucleotide position 677, causing the serine (S) at amino acid position 226 to be replaced by a leucine (L). 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
0.080
BayesDel_noAF
Benign
-0.83
Cadd
Benign
12
Dann
Benign
0.73
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.78
T
MetaRNN
Benign
0.020
T
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.34
T
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.053
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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: rs201617000; hg19: chr2-241512534; COSMIC: COSV99549337; COSMIC: COSV99549337; API