10-119500160-C-T

Position:

• chr10-119500160-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005339.2(RGS10):​c.499G>A​(p.Asp167Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RGS10 NM_001005339.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.239212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS10	NM_001005339.2	c.499G>A	p.Asp167Asn	missense_variant	5/5	ENST00000369103.3
RGS10	NM_002925.4	c.457G>A	p.Asp153Asn	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS10	ENST00000369103.3	c.499G>A	p.Asp167Asn	missense_variant	5/5	1	NM_001005339.2	P1
RGS10	ENST00000369101.7	c.475G>A	p.Asp159Asn	missense_variant	4/4	1
RGS10	ENST00000392865.5	c.457G>A	p.Asp153Asn	missense_variant	5/5	1
RGS10	ENST00000469575.1	n.236G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.499G>A (p.D167N) alteration is located in exon 5 (coding exon 5) of the RGS10 gene. This alteration results from a G to A substitution at nucleotide position 499, causing the aspartic acid (D) at amino acid position 167 to be replaced by an asparagine (N). 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	0.098
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.12
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.64	P;P;P
Vest4		0.13
MutPred		0.24		.;Gain of MoRF binding (P = 0.0601);.;
MVP		0.62
MPC		0.69
ClinPred		0.77	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
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: rs778481186; hg19: chr10-121259672;