10-119527403-C-G

Variant names:

• chr10-119527403-C-G
• rs201036573
• NM_001005339.2:c.71G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001005339.2(RGS10):​c.71G>C​(p.Ser24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RGS10 NM_001005339.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

RGS10 (HGNC:9992): (regulator of G protein signaling 10) 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 10 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. This protein associates specifically with the activated forms of the two related G-protein subunits, G-alphai3 and G-alphaz but fails to interact with the structurally and functionally distinct G-alpha subunits. Regulator of G protein signaling 10 protein is localized in the nucleus. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity RGS10_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.022916853).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS10	NM_001005339.2	c.71G>C	p.Ser24Thr	missense_variant	Exon 2 of 5	ENST00000369103.3	NP_001005339.1
RGS10	NM_002925.4	c.29G>C	p.Ser10Thr	missense_variant	Exon 2 of 5		NP_002916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS10	ENST00000369103.3	c.71G>C	p.Ser24Thr	missense_variant	Exon 2 of 5	1	NM_001005339.2	ENSP00000358099.2
RGS10	ENST00000369101.7	c.47G>C	p.Ser16Thr	missense_variant	Exon 1 of 4	1		ENSP00000358097.3
RGS10	ENST00000392865.5	c.29G>C	p.Ser10Thr	missense_variant	Exon 2 of 5	1		ENSP00000376605.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152268 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251388 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000597

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: 0.0000662

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152386 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74520

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

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: 0.00

Bravo AF: 0.0000869

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71G>C (p.S24T) alteration is located in exon 2 (coding exon 2) of the RGS10 gene. This alteration results from a G to C substitution at nucleotide position 71, causing the serine (S) at amino acid position 24 to be replaced by a threonine (T). 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	0.065
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.23	.;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.17
MutPred		0.22		.;Loss of phosphorylation at S16 (P = 0.0522);.;
MVP		0.24
MPC		0.64
ClinPred		0.034	T
GERP RS		3.7
Varity_R		0.095
gMVP		0.50

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: rs201036573; hg19: chr10-121286915;