1-192578225-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002922.4(RGS1):c.284G>T(p.Gly95Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G95D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGS1 NM_002922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14

Genes affected

RGS1 (HGNC:9991): (regulator of G protein signaling 1) This gene encodes a member of the regulator of G-protein signalling family. This protein is located on the cytosolic side of the plasma membrane and contains a conserved, 120 amino acid motif called the RGS domain. The protein attenuates the signalling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein (GAP), increasing the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS1	NM_002922.4	c.284G>T	p.Gly95Val	missense_variant	4/5	ENST00000367459.8
LOC105371664	XR_002958418.2	n.288-11009C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS1	ENST00000367459.8	c.284G>T	p.Gly95Val	missense_variant	4/5	1	NM_002922.4	P1
	ENST00000644134.1	n.468-8921C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Nov 29, 2023

The c.284G>T (p.G95V) alteration is located in exon 4 (coding exon 4) of the RGS1 gene. This alteration results from a G to T substitution at nucleotide position 284, causing the glycine (G) at amino acid position 95 to be replaced by a valine (V). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	27
Dann	Benign	0.97
DEOGEN2	Uncertain	0.51	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-8.8	D;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.93		Loss of disorder (P = 0.0761);Loss of disorder (P = 0.0761);
MVP		0.61
MPC		0.46
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.73

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: rs748410689; hg19: chr1-192547355;