16-2262288-G-T

Variant names:

• chr16-2262288-G-T
• NM_080594.4:c.666C>A

Variant summary

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

The NM_080594.4(RNPS1):​c.666C>A​(p.His222Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNPS1 NM_080594.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

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 rank	MANE	Protein	UniProt
RNPS1	NM_080594.4	c.666C>A	p.His222Gln	missense_variant	Exon 6 of 8	ENST00000320225.10	NP_542161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNPS1	ENST00000320225.10	c.666C>A	p.His222Gln	missense_variant	Exon 6 of 8	1	NM_080594.4	ENSP00000315859.5
RNPS1	ENST00000301730.12	c.666C>A	p.His222Gln	missense_variant	Exon 7 of 9	2		ENSP00000301730.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.666C>A (p.H222Q) alteration is located in exon 6 (coding exon 5) of the RNPS1 gene. This alteration results from a C to A substitution at nucleotide position 666, causing the histidine (H) at amino acid position 222 to be replaced by a glutamine (Q). 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	1.0
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T;T;.;T;T;T;T;.;T;T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;.;D;.;.;D;.;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.72	N;N;.;.;N;.;N;.;N;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.7	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;.;D;D;D;D;D;D;.;.;.
Polyphen		1.0	D;D;D;.;D;.;D;.;D;.;.;.
Vest4		0.67
MutPred		0.37		Gain of ubiquitination at K218 (P = 0.0743);Gain of ubiquitination at K218 (P = 0.0743);.;.;Gain of ubiquitination at K218 (P = 0.0743);.;Gain of ubiquitination at K218 (P = 0.0743);.;Gain of ubiquitination at K218 (P = 0.0743);.;Gain of ubiquitination at K218 (P = 0.0743);Gain of ubiquitination at K218 (P = 0.0743);
MVP		0.50
MPC		1.3
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.92
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2312289;