rs104894039

Positions:

• chr7-33095391-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_203288.2(RP9):​c.509A>G​(p.Asp170Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000158 in 152,324 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 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RP9 NM_203288.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.10

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22453621).
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP9	NM_203288.2	c.509A>G	p.Asp170Gly	missense_variant	6/6	ENST00000297157.8	NP_976033.1
LOC124901610	XR_007060277.1	n.1318T>C		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP9	ENST00000297157.8	c.509A>G	p.Asp170Gly	missense_variant	6/6	1	NM_203288.2	ENSP00000297157	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000118

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.0000638 AC: 16 AN: 250914 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135622

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000527 AC: 77 AN: 1461376 Hom.: 0 Cov.: 32 AF XY: 0.0000591 AC XY: 43 AN XY: 726984

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74476

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000948

Bravo AF: 0.000208

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2006

- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	0.042
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.62
Sift	Benign	0.55	T;T
Sift4G	Benign	0.088	T;.
Polyphen		0.36	B;.
Vest4		0.74
MVP		0.83
MPC		1.4
ClinPred		0.14	T
GERP RS		3.8
Varity_R		0.29
gMVP		0.026

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs104894039; hg19: chr7-33135003; COSMIC: COSV99778078; COSMIC: COSV99778078;