chr16-2263156-G-A

Position:

• chr16-2263156-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080594.4(RNPS1):​c.359C>T​(p.Ser120Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RNPS1 NM_080594.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21

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]

RNPS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNPS1	NM_080594.4	c.359C>T	p.Ser120Phe	missense_variant	4/8	ENST00000320225.10	NP_542161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNPS1	ENST00000320225.10	c.359C>T	p.Ser120Phe	missense_variant	4/8	1	NM_080594.4	ENSP00000315859.5
RNPS1	ENST00000301730.12	c.359C>T	p.Ser120Phe	missense_variant	5/9	2		ENSP00000301730.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461540 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727052

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2024

The c.359C>T (p.S120F) alteration is located in exon 4 (coding exon 3) of the RNPS1 gene. This alteration results from a C to T substitution at nucleotide position 359, causing the serine (S) at amino acid position 120 to be replaced by a phenylalanine (F). 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	0.62
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Benign	0.26	T;T;.;T;T;.;T;T;T;T;T;T;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	.;.;D;.;.;T;D;D;D;D;D;T;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	2.0	M;M;.;M;M;.;M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.29
Sift	Benign	0.13	T;T;T;T;T;D;T;T;T;T;T;T;T;.
Sift4G	Uncertain	0.052	T;T;.;T;T;D;T;.;.;.;.;D;.;D
Polyphen		0.97	D;D;D;D;D;.;D;.;.;.;.;.;.;.
Vest4		0.47
MutPred		0.36		Loss of phosphorylation at S120 (P = 0);Loss of phosphorylation at S120 (P = 0);.;Loss of phosphorylation at S120 (P = 0);Loss of phosphorylation at S120 (P = 0);.;Loss of phosphorylation at S120 (P = 0);.;Loss of phosphorylation at S120 (P = 0);Loss of phosphorylation at S120 (P = 0);Loss of phosphorylation at S120 (P = 0);Loss of phosphorylation at S120 (P = 0);Loss of phosphorylation at S120 (P = 0);Loss of phosphorylation at S120 (P = 0);
MVP		0.49
MPC		0.51
ClinPred		0.54	D
GERP RS		6.0
Varity_R		0.34
gMVP		0.51

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

Other links and lift over

dbSNP: rs2093610275; hg19: chr16-2313157;