1-192578269-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002922.4(RGS1):c.328G>A(p.Glu110Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RGS1 NM_002922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS1	NM_002922.4	c.328G>A	p.Glu110Lys	missense_variant	4/5	ENST00000367459.8
LOC105371664	XR_002958418.2	n.288-11053C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS1	ENST00000367459.8	c.328G>A	p.Glu110Lys	missense_variant	4/5	1	NM_002922.4	P1
	ENST00000644134.1	n.468-8965C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460838 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 28, 2023

The c.328G>A (p.E110K) alteration is located in exon 4 (coding exon 4) of the RGS1 gene. This alteration results from a G to A substitution at nucleotide position 328, causing the glutamic acid (E) at amino acid position 110 to be replaced by a lysine (K). 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	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.78		Gain of methylation at E110 (P = 0.008);Gain of methylation at E110 (P = 0.008);
MVP		0.64
MPC		0.44
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-192547399;