NM_080594.4:c.875G>A

Variant names:

• chr16-2254007-C-T
• rs748703751
• NM_080594.4:c.875G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_080594.4(RNPS1):​c.875G>A​(p.Arg292His) variant causes a missense change. The variant allele was found at a frequency of 0.0000392 in 1,379,156 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R292C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (2 hom.)
• Consequence: RNPS1 NM_080594.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.35
• Publications: 0 publications found

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]

ENSG00000299317 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10576749).
• BS2: High AC in GnomAdExome4 at 54 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080594.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPS1	NM_080594.4	MANE Select	c.875G>A	p.Arg292His	missense	Exon 8 of 8	NP_542161.1	Q15287-1
	RNPS1	NM_001286625.1		c.875G>A	p.Arg292His	missense	Exon 8 of 8	NP_001273554.1	D3DU92
	RNPS1	NM_006711.5		c.875G>A	p.Arg292His	missense	Exon 8 of 8	NP_006702.1	Q15287-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPS1	ENST00000320225.10	TSL:1 MANE Select	c.875G>A	p.Arg292His	missense	Exon 8 of 8	ENSP00000315859.5	Q15287-1
	RNPS1	ENST00000301730.12	TSL:2	c.875G>A	p.Arg292His	missense	Exon 9 of 9	ENSP00000301730.8	Q15287-1
	RNPS1	ENST00000397086.6	TSL:1	c.875G>A	p.Arg292His	missense	Exon 8 of 8	ENSP00000380275.2	Q15287-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000445 AC: 6 AN: 134774 AF XY: 0.0000566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000962

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000392 AC: 54 AN: 1379156 Hom.: 2 Cov.: 30 AF XY: 0.0000398 AC XY: 27 AN XY: 678710

African (AFR) AF: 0.00 AC: 0 AN: 30724

American (AMR) AF: 0.00 AC: 0 AN: 32424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23706

East Asian (EAS) AF: 0.0000848 AC: 3 AN: 35374

South Asian (SAS) AF: 0.000418 AC: 32 AN: 76496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.0000168 AC: 18 AN: 1069100

Other (OTH) AF: 0.0000175 AC: 1 AN: 57052

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000378 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.11	T
PhyloP100		5.3
PROVEAN	Benign	1.8	N
Sift	Benign	0.54	T
Vest4		0.30
MVP		0.42
ClinPred		0.32	T
GERP RS		4.2
Varity_R		0.21
Mutation Taster		=36/64	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

Other links and lift over

dbSNP: rs748703751; hg19: chr16-2304008;