16-2262840-G-C

Position:

• chr16-2262840-G-C

Variant summary

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

The NM_080594.4(RNPS1):​c.422C>G​(p.Ser141Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNPS1 NM_080594.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.46

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]

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.422C>G	p.Ser141Cys	missense_variant, splice_region_variant	5/8	ENST00000320225.10	NP_542161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNPS1	ENST00000320225.10	c.422C>G	p.Ser141Cys	missense_variant, splice_region_variant	5/8	1	NM_080594.4	ENSP00000315859	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 26, 2023

The c.422C>G (p.S141C) alteration is located in exon 5 (coding exon 4) of the RNPS1 gene. This alteration results from a C to G substitution at nucleotide position 422, causing the serine (S) at amino acid position 141 to be replaced by a cysteine (C). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;T;.;T;T;.;T;T;T;T;T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;D;.;.;D;D;D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.062	T;T;T;T;T;D;T;D;T;D;D;D
Sift4G	Uncertain	0.018	D;D;.;D;D;D;D;.;.;.;.;D
Polyphen		0.99	D;D;D;D;D;.;D;.;.;.;.;.
Vest4		0.52
MutPred		0.30		Loss of phosphorylation at S141 (P = 2e-04);Loss of phosphorylation at S141 (P = 2e-04);.;Loss of phosphorylation at S141 (P = 2e-04);Loss of phosphorylation at S141 (P = 2e-04);.;Loss of phosphorylation at S141 (P = 2e-04);.;Loss of phosphorylation at S141 (P = 2e-04);Loss of phosphorylation at S141 (P = 2e-04);Loss of phosphorylation at S141 (P = 2e-04);Loss of phosphorylation at S141 (P = 2e-04);
MVP		0.47
MPC		0.45
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.60
gMVP		0.66

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: rs2093608722; hg19: chr16-2312841;