8-53939660-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_170587.4(RGS20):c.595G>A(p.Gly199Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000483 in 1,588,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: RGS20 NM_170587.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

Genes affected

RGS20 (HGNC:14600): (regulator of G protein signaling 20) The protein encoded by this gene belongs to the family of regulator of G protein signaling (RGS) proteins, which are regulatory and structural components of G protein-coupled receptor complexes. RGS proteins inhibit signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound forms. This protein selectively binds to G(z)-alpha and G(alpha)-i2 subunits, and regulates their signaling activities. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006878078).
• BS2: High AC in GnomAd at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS20	NM_170587.4	c.595G>A	p.Gly199Arg	missense_variant	3/6	ENST00000297313.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS20	ENST00000297313.8	c.595G>A	p.Gly199Arg	missense_variant	3/6	1	NM_170587.4

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000668 AC: 137 AN: 204968 Hom.: 0 AF XY: 0.000740 AC XY: 81 AN XY: 109446

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.000779

Gnomad ASJ exome AF: 0.00166

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.0000551

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000493 AC: 708 AN: 1436498 Hom.: 1 Cov.: 31 AF XY: 0.000552 AC XY: 393 AN XY: 711692

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000755

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000913

Gnomad4 FIN exome AF: 0.000117

Gnomad4 NFE exome AF: 0.000454

Gnomad4 OTH exome AF: 0.000672

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74464

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000721 Hom.: 0

Bravo AF: 0.000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000584 AC: 70

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.595G>A (p.G199R) alteration is located in exon 3 (coding exon 3) of the RGS20 gene. This alteration results from a G to A substitution at nucleotide position 595, causing the glycine (G) at amino acid position 199 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	16
Dann	Benign	0.92
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	N;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.068	T;T;T
Polyphen		0.48	P;B;B
Vest4		0.22
MutPred		0.19		Gain of solvent accessibility (P = 0.019);.;.;
MVP		0.64
MPC		0.57
ClinPred		0.014	T
GERP RS		3.0
Varity_R		0.14
gMVP		0.31

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: rs145171609; hg19: chr8-54852220; COSMIC: COSV52017661;