chr17-65225096-G-A

Position:

• chr17-65225096-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262406.10(RGS9):​c.1502G>A​(p.Arg501His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,616 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R501L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 32)
  • Exomes 𝑓: 0.018 (277 hom.)
• Consequence: RGS9 ENST00000262406.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.604

Genes affected

RGS9 (HGNC:10004): (regulator of G protein signaling 9) This gene encodes a member of the RGS family of GTPase activating proteins that function in various signaling pathways by accelerating the deactivation of G proteins. This protein is anchored to photoreceptor membranes in retinal cells and deactivates G proteins in the rod and cone phototransduction cascades. Mutations in this gene result in bradyopsia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004187554).
• BP6: Variant 17-65225096-G-A is Benign according to our data. Variant chr17-65225096-G-A is described in ClinVar as [Benign]. Clinvar id is 94379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65225096-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1735/152086) while in subpopulation NFE AF= 0.0195 (1327/67948). AF 95% confidence interval is 0.0187. There are 15 homozygotes in gnomad4. There are 791 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGS9	NM_003835.4	c.1502G>A	p.Arg501His	missense_variant	18/19	ENST00000262406.10	NP_003826.2
RGS9	NM_001081955.3	c.1493G>A	p.Arg498His	missense_variant	18/19		NP_001075424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS9	ENST00000262406.10	c.1502G>A	p.Arg501His	missense_variant	18/19	1	NM_003835.4	ENSP00000262406	P4

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1735 AN: 151970 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00368

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0107 AC: 2668 AN: 249178 Hom.: 33 AF XY: 0.0104 AC XY: 1407 AN XY: 135228

Gnomad AFR exome AF: 0.00329

Gnomad AMR exome AF: 0.00559

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.000723

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00879

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.00941

GnomAD4 exome AF: 0.0175 AC: 25623 AN: 1461530 Hom.: 277 Cov.: 32 AF XY: 0.0169 AC XY: 12288 AN XY: 727092

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00184

Gnomad4 FIN exome AF: 0.00879

Gnomad4 NFE exome AF: 0.0214

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0114 AC: 1735 AN: 152086 Hom.: 15 Cov.: 32 AF XY: 0.0106 AC XY: 791 AN XY: 74342

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.00857

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0155 Hom.: 16

Bravo AF: 0.0106

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00466 AC: 19

ESP6500EA AF: 0.0181 AC: 152

ExAC AF: 0.0108 AC: 1311

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0149

EpiControl AF: 0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0067	T;.;.;T
Eigen	Benign	0.027
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.85	T;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;.;L
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.26	.;.;N;N
REVEL	Benign	0.047
Sift	Uncertain	0.0020	.;.;D;D
Sift4G	Uncertain	0.034	.;D;D;D
Polyphen		0.98, 0.96	.;.;D;D
Vest4		0.052, 0.19, 0.26
MPC		0.23
ClinPred		0.019	T
GERP RS		3.9
Varity_R		0.15
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34797451; hg19: chr17-63221214; COSMIC: COSV99068753;