1-163069317-G-T

Variant names:

• chr1-163069317-G-T
• rs370032435
• ENST00000421743.6:c.124G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001113381.1(RGS4):​c.-168G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,551,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: RGS4 NM_001113381.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.78
• Publications: 2 publications found

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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010190368).
• BS2: High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113381.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS4	NM_001113381.1		c.-168G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001106852.1
	RGS4	NM_001102445.3		c.124G>T	p.Gly42Cys	missense	Exon 2 of 6	NP_001095915.1
	RGS4	NM_001113381.1		c.-168G>T		5_prime_UTR	Exon 1 of 4	NP_001106852.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS4	ENST00000421743.6	TSL:1	c.124G>T	p.Gly42Cys	missense	Exon 2 of 6	ENSP00000397181.2
	RGS4	ENST00000527393.5	TSL:4	n.146G>T		non_coding_transcript_exon	Exon 2 of 5
	RGS4	ENST00000367909.11	TSL:1 MANE Select	c.-168G>T		upstream_gene	N/A	ENSP00000356885.6

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000961 AC: 15 AN: 156114 AF XY: 0.000109

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.0000806

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 27 AN: 1399234 Hom.: 0 Cov.: 33 AF XY: 0.0000217 AC XY: 15 AN XY: 690190

African (AFR) AF: 0.000697 AC: 22 AN: 31572

American (AMR) AF: 0.0000560 AC: 2 AN: 35714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49296

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078810

Other (OTH) AF: 0.0000172 AC: 1 AN: 57992

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74370

African (AFR) AF: 0.000674 AC: 28 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00114 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000459 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.1
DANN	Benign	0.96
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.11
Sift	Uncertain	0.014	D
Vest4		0.098
MVP		0.17
MPC		0.24
ClinPred		0.019	T
GERP RS		0.39
PromoterAI		-0.018	Neutral
gMVP		0.23
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs370032435; hg19: chr1-163039107;