8-53879382-C-A

Variant summary

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

The NM_170587.4(RGS20):c.290C>A(p.Ala97Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,611,398 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A97T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: RGS20 NM_170587.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0700

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=0.024302661).
• BS2: High AC in GnomAd at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS20	NM_170587.4	c.290C>A	p.Ala97Asp	missense_variant	2/6	ENST00000297313.8
RGS20	NM_001286673.2	c.165+27318C>A		intron_variant
RGS20	NM_001286674.2	c.35+27318C>A		intron_variant
RGS20	NM_001286675.2	c.35+27318C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS20	ENST00000297313.8	c.290C>A	p.Ala97Asp	missense_variant	2/6	1	NM_170587.4
RGS20	ENST00000344277.10	c.165+27318C>A		intron_variant		1
RGS20	ENST00000517659.5	c.165+27318C>A		intron_variant, NMD_transcript_variant		1
RGS20	ENST00000523280.1	c.165+27318C>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000187 AC: 46 AN: 246362 Hom.: 0 AF XY: 0.000164 AC XY: 22 AN XY: 134070

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000894

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1459136 Hom.: 0 Cov.: 32 AF XY: 0.0000992 AC XY: 72 AN XY: 725984

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74442

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000356 Hom.: 0

Bravo AF: 0.000552

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

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

Feb 27, 2023

The c.290C>A (p.A97D) alteration is located in exon 2 (coding exon 2) of the RGS20 gene. This alteration results from a C to A substitution at nucleotide position 290, causing the alanine (A) at amino acid position 97 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.017	D
Polyphen		0.94	P
Vest4		0.34
MVP		0.78
MPC		0.88
ClinPred		0.066	T
GERP RS		3.5
Varity_R		0.39
gMVP		0.25

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: rs144772329; hg19: chr8-54791942;