1-163074337-G-A

Position:

• chr1-163074337-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005613.6(RGS4):​c.395G>A​(p.Cys132Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGS4 NM_005613.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

Genes affected

RGS4 (HGNC:10000): (regulator of G protein signaling 4) Regulator of G protein signaling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 4 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. Regulator of G protein signaling 4 protein is 37% identical to RGS1 and 97% identical to rat Rgs4. This protein negatively regulate signaling upstream or at the level of the heterotrimeric G protein and is localized in the cytoplasm. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13471171).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS4	NM_005613.6	c.395G>A	p.Cys132Tyr	missense_variant	5/5	ENST00000367909.11
RGS4	NM_001102445.3	c.686G>A	p.Cys229Tyr	missense_variant	6/6
RGS4	NM_001113380.1	c.341G>A	p.Cys114Tyr	missense_variant	5/5
RGS4	NM_001113381.1	c.228G>A	p.Leu76=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS4	ENST00000367909.11	c.395G>A	p.Cys132Tyr	missense_variant	5/5	1	NM_005613.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 10, 2023

The c.686G>A (p.C229Y) alteration is located in exon 6 (coding exon 6) of the RGS4 gene. This alteration results from a G to A substitution at nucleotide position 686, causing the cysteine (C) at amino acid position 229 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.38
DEOGEN2	Benign	0.23	.;T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;T;.;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.92	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	3.1	N;N;N;N;N
REVEL	Benign	0.084
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T
Polyphen		0.0030	.;B;.;.;.
Vest4		0.20
MutPred		0.30		.;Gain of phosphorylation at C132 (P = 0.0298);.;.;.;
MVP		0.29
MPC		0.69
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.10
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-163044127; COSMIC: COSV100905538; COSMIC: COSV100905538;