16-2263130-G-A

Position:

• chr16-2263130-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_080594.4(RNPS1):​c.385C>T​(p.Arg129Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,140 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 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RNPS1 NM_080594.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38487005).
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNPS1	NM_080594.4	c.385C>T	p.Arg129Cys	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.385C>T	p.Arg129Cys	missense_variant	4/8	1	NM_080594.4	ENSP00000315859	A1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000323 AC: 8 AN: 248026 Hom.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134514

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460984 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 726760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

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

May 21, 2024

The c.385C>T (p.R129C) 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 385, causing the arginine (R) at amino acid position 129 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	Pathogenic	0.80
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.;T;T;.;T;T;T;T;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;.;D;.;.;T;D;D;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;M;.;M;M;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;.;D;D;D;D;.;.;.;.;T;.
Polyphen		0.82	P;P;P;P;P;.;P;.;.;.;.;.;.
Vest4		0.52
MutPred		0.36		Loss of methylation at R129 (P = 0.0151);Loss of methylation at R129 (P = 0.0151);.;Loss of methylation at R129 (P = 0.0151);Loss of methylation at R129 (P = 0.0151);.;Loss of methylation at R129 (P = 0.0151);.;Loss of methylation at R129 (P = 0.0151);Loss of methylation at R129 (P = 0.0151);Loss of methylation at R129 (P = 0.0151);Loss of methylation at R129 (P = 0.0151);Loss of methylation at R129 (P = 0.0151);
MVP		0.51
MPC		0.63
ClinPred		0.58	D
GERP RS		5.1
Varity_R		0.36
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: rs779084671; hg19: chr16-2313131;