16-2264312-G-T

Variant names:

• chr16-2264312-G-T
• rs140623716
• NM_080594.4:c.91C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_080594.4(RNPS1):​c.91C>A​(p.Arg31Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNPS1 NM_080594.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.74
• Publications: 6 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3029141).

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.91C>A	p.Arg31Ser	missense	Exon 3 of 8	NP_542161.1	Q15287-1
	RNPS1	NM_001286625.1		c.91C>A	p.Arg31Ser	missense	Exon 3 of 8	NP_001273554.1	D3DU92
	RNPS1	NM_006711.5		c.91C>A	p.Arg31Ser	missense	Exon 3 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.91C>A	p.Arg31Ser	missense	Exon 3 of 8	ENSP00000315859.5	Q15287-1
	RNPS1	ENST00000301730.12	TSL:2	c.91C>A	p.Arg31Ser	missense	Exon 4 of 9	ENSP00000301730.8	Q15287-1
	RNPS1	ENST00000397086.6	TSL:1	c.91C>A	p.Arg31Ser	missense	Exon 3 of 8	ENSP00000380275.2	Q15287-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.71	T
Polyphen		0.96	D
Vest4		0.56
MutPred		0.35		Gain of phosphorylation at R31 (P = 3e-04)
MVP		0.68
MPC		0.53
ClinPred		0.85	D
GERP RS		5.7
PromoterAI		-0.027	Neutral
Varity_R		0.47
gMVP		0.33
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140623716; hg19: chr16-2314313;