7-33095292-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_203288.2(RP9):c.608A>T(p.Lys203Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RP9 NM_203288.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

Genes affected

RP9 (HGNC:10288): (RP9 pre-mRNA splicing factor) The protein encoded by this gene can be bound and phosphorylated by the protooncogene PIM1 product, a serine/threonine protein kinase . This protein localizes in nuclear speckles containing the splicing factors, and has a role in pre-mRNA splicing. CBF1-interacting protein (CIR), a corepressor of CBF1, can also bind to this protein and effects alternative splicing. Mutations in this gene result in autosomal dominant retinitis pigmentosa-9. This gene has a pseudogene (GeneID: 441212), which is located in tandem array approximately 166 kb distal to this gene. [provided by RefSeq, Sep 2009]

LOC124901610 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31101316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP9	NM_203288.2	c.608A>T	p.Lys203Met	missense_variant	6/6	ENST00000297157.8
LOC124901610	XR_007060277.1	n.1219T>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP9	ENST00000297157.8	c.608A>T	p.Lys203Met	missense_variant	6/6	1	NM_203288.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2017

The K203M variant in the RP9 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K203M variant is not observed in large population cohorts (Lek et al., 2016). The K203M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret K203M as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.32
MutPred		0.26		Loss of methylation at K203 (P = 0.0025);
MVP		0.79
MPC		1.2
ClinPred		0.93	D
GERP RS		2.7
Varity_R		0.17
gMVP		0.025

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: rs1554296572; hg19: chr7-33134904;