chr1-163074481-C-G

Position:

chr1-163074481-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000367909.11(RGS4):c.539C>G(p.Pro180Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,780 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. P180L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RGS4
ENST00000367909.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.701

Variant links:

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]

RGS4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.090328634).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RGS4	NM_005613.6 linkuse as main transcript	c.539C>G	p.Pro180Arg	missense_variant	5/5	ENST00000367909.11	NP_005604.1
RGS4	NM_001102445.3 linkuse as main transcript	c.830C>G	p.Pro277Arg	missense_variant	6/6		NP_001095915.1
RGS4	NM_001113380.1 linkuse as main transcript	c.485C>G	p.Pro162Arg	missense_variant	5/5		NP_001106851.1
RGS4	NM_001113381.1 linkuse as main transcript	c.*90C>G		3_prime_UTR_variant	4/4		NP_001106852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS4	ENST00000367909.11 linkuse as main transcript	c.539C>G	p.Pro180Arg	missense_variant	5/5	1	NM_005613.6	ENSP00000356885	P1	P49798-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.830C>G (p.P277R) alteration is located in exon 6 (coding exon 6) of the RGS4 gene. This alteration results from a C to G substitution at nucleotide position 830, causing the proline (P) at amino acid position 277 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

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.30

.;T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.64

T;T;.;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.090

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.40

.;N;.;.

MutationTaster

Benign

0.50

D;D;D;D;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.050

N;N;N;N

REVEL

Benign

0.032

Sift

Benign

0.061

T;T;T;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.0080

.;B;.;.

Vest4

0.19

MutPred

0.30

.;Gain of MoRF binding (P = 0.0025);.;.;

MVP

0.46

MPC

0.24

ClinPred

0.046

GERP RS

1.9

Varity_R

0.022

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over