16-2253989-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_080594.4(RNPS1):​c.893G>A​(p.Arg298His) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,547,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RNPS1
NM_080594.4 missense

Scores

2
4
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.04

Publications

0 publications found
Variant links:
Genes affected
RNPS1 (HGNC:10080): (RNA binding protein with serine rich domain 1) This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. This protein contains many serine residues. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.28706783).
BS2
High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RNPS1NM_080594.4 linkc.893G>A p.Arg298His missense_variant Exon 8 of 8 ENST00000320225.10 NP_542161.1 Q15287-1D3DU92

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNPS1ENST00000320225.10 linkc.893G>A p.Arg298His missense_variant Exon 8 of 8 1 NM_080594.4 ENSP00000315859.5 Q15287-1
RNPS1ENST00000301730.12 linkc.893G>A p.Arg298His missense_variant Exon 9 of 9 2 ENSP00000301730.8 Q15287-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000252
AC:
4
AN:
158456
AF XY:
0.0000357
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000128
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000157
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000165
AC:
23
AN:
1394968
Hom.:
0
Cov.:
30
AF XY:
0.0000160
AC XY:
11
AN XY:
687518
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31346
American (AMR)
AF:
0.0000855
AC:
3
AN:
35080
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24596
East Asian (EAS)
AF:
0.0000835
AC:
3
AN:
35928
South Asian (SAS)
AF:
0.0000635
AC:
5
AN:
78734
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49472
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5622
European-Non Finnish (NFE)
AF:
0.0000111
AC:
12
AN:
1076460
Other (OTH)
AF:
0.00
AC:
0
AN:
57730
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 28, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.893G>A (p.R298H) alteration is located in exon 8 (coding exon 7) of the RNPS1 gene. This alteration results from a G to A substitution at nucleotide position 893, causing the arginine (R) at amino acid position 298 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
Pathogenic
0.97
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.013
T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.29
T
PhyloP100
7.0
PROVEAN
Benign
-0.62
N
Sift
Uncertain
0.0040
D
Vest4
0.31
MVP
0.51
ClinPred
0.41
T
GERP RS
5.2
Varity_R
0.45
Mutation Taster
=14/86
disease causing

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

Other links and lift over

dbSNP: rs751933749; hg19: chr16-2303990; API