1-182648213-G-T

Variant names:

• chr1-182648213-G-T
• rs34360993
• NM_001102450.3:c.284C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001102450.3(RGS8):​c.284C>A​(p.Thr95Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T95I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RGS8 NM_001102450.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92
• Publications: 6 publications found

Genes affected

RGS8 (HGNC:16810): (regulator of G protein signaling 8) This gene is a member of the regulator of G protein signaling (RGS) family and encodes a protein with a single RGS domain. Regulator of G protein signaling (RGS) proteins are regulatory and structural components of G protein-coupled receptor complexes. They accelerate transit through the cycle of GTP binding and hydrolysis to GDP, thereby terminating signal transduction, but paradoxically, also accelerate receptor-stimulated activation. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41594034).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102450.3. 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
	RGS8	NM_001102450.3	MANE Select	c.284C>A	p.Thr95Asn	missense	Exon 7 of 8	NP_001095920.1	P57771-1
	RGS8	NM_033345.4		c.338C>A	p.Thr113Asn	missense	Exon 6 of 7	NP_203131.1	P57771-2
	RGS8	NM_001369564.2		c.284C>A	p.Thr95Asn	missense	Exon 5 of 6	NP_001356493.1	P57771-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS8	ENST00000515211.2	TSL:4 MANE Select	c.284C>A	p.Thr95Asn	missense	Exon 7 of 8	ENSP00000511884.1	P57771-1
	RGS8	ENST00000258302.8	TSL:1	c.338C>A	p.Thr113Asn	missense	Exon 5 of 6	ENSP00000258302.4	P57771-2
	RGS8	ENST00000367557.8	TSL:1	c.284C>A	p.Thr95Asn	missense	Exon 6 of 7	ENSP00000356528.4	P57771-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461472 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727028

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.18
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.45
MutPred		0.47		Gain of ubiquitination at K94 (P = 0.1278)
MVP		0.17
MPC		1.2
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.71
gMVP		0.46
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs34360993; hg19: chr1-182617348;