1-163074465-C-A

Variant names:

• chr1-163074465-C-A
• rs915888658
• NM_005613.6:c.523C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005613.6(RGS4):​c.523C>A​(p.Leu175Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RGS4 NM_005613.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.794

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23354152).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS4	NM_005613.6	c.523C>A	p.Leu175Ile	missense_variant	Exon 5 of 5	ENST00000367909.11	NP_005604.1
RGS4	NM_001102445.3	c.814C>A	p.Leu272Ile	missense_variant	Exon 6 of 6		NP_001095915.1
RGS4	NM_001113380.1	c.469C>A	p.Leu157Ile	missense_variant	Exon 5 of 5		NP_001106851.1
RGS4	NM_001113381.1	c.*74C>A		3_prime_UTR_variant	Exon 4 of 4		NP_001106852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS4	ENST00000367909.11	c.523C>A	p.Leu175Ile	missense_variant	Exon 5 of 5	1	NM_005613.6	ENSP00000356885.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251352 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461656 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727148

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33460

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44714

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26126

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39694

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000108 AC: 12 AN: 1111834

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147054 AN: 0.0000147054

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.814C>A (p.L272I) alteration is located in exon 6 (coding exon 6) of the RGS4 gene. This alteration results from a C to A substitution at nucleotide position 814, causing the leucine (L) at amino acid position 272 to be replaced by an isoleucine (I). 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	-0.19	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	.;T;.;.
Eigen	Benign	0.068
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.70	T;T;.;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;T;D;D
Sift4G	Benign	0.062	T;T;T;T
Polyphen		0.057	.;B;.;.
Vest4		0.41
MutPred		0.55		.;Loss of disorder (P = 0.0946);.;.;
MVP		0.45
MPC		0.53
ClinPred		0.53	D
GERP RS		4.2
Varity_R		0.13
gMVP		0.14
Mutation Taster		=88/12	polymorphism

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: rs915888658; hg19: chr1-163044255;