NM_080594.4:c.878G>A

Variant names:

• chr16-2254004-C-T
• rs781643382
• NM_080594.4:c.878G>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.878G>A​(p.Arg293His) variant causes a missense change. The variant allele was found at a frequency of 0.0000391 in 1,534,198 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: RNPS1 NM_080594.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05
• Publications: 1 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=0.19689932).
• BS2: High AC in GnomAd4 at 5 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.878G>A	p.Arg293His	missense	Exon 8 of 8	NP_542161.1	Q15287-1
	RNPS1	NM_001286625.1		c.878G>A	p.Arg293His	missense	Exon 8 of 8	NP_001273554.1	D3DU92
	RNPS1	NM_006711.5		c.878G>A	p.Arg293His	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.878G>A	p.Arg293His	missense	Exon 8 of 8	ENSP00000315859.5	Q15287-1
	RNPS1	ENST00000301730.12	TSL:2	c.878G>A	p.Arg293His	missense	Exon 9 of 9	ENSP00000301730.8	Q15287-1
	RNPS1	ENST00000397086.6	TSL:1	c.878G>A	p.Arg293His	missense	Exon 8 of 8	ENSP00000380275.2	Q15287-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000506 AC: 7 AN: 138336 AF XY: 0.0000137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000398 AC: 55 AN: 1382014 Hom.: 0 Cov.: 30 AF XY: 0.0000382 AC XY: 26 AN XY: 680390

African (AFR) AF: 0.00 AC: 0 AN: 30820

American (AMR) AF: 0.00 AC: 0 AN: 32742

Ashkenazi Jewish (ASJ) AF: 0.0000419 AC: 1 AN: 23888

East Asian (EAS) AF: 0.00 AC: 0 AN: 35492

South Asian (SAS) AF: 0.00 AC: 0 AN: 76856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.0000495 AC: 53 AN: 1070636

Other (OTH) AF: 0.0000175 AC: 1 AN: 57146

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000374 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	0.92
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.20	T
PhyloP100		7.0
PROVEAN	Benign	-1.1	N
Sift	Uncertain	0.028	D
Vest4		0.24
MVP		0.38
ClinPred		0.27	T
GERP RS		5.2
Varity_R		0.31
Mutation Taster		=37/63	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: rs781643382; hg19: chr16-2304005; COSMIC: COSV99042090; COSMIC: COSV99042090;