16-270567-C-T

Variant summary

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

The NM_183337.3(RGS11):c.1162G>A(p.Val388Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000021 (0 hom.)
• Consequence: RGS11 NM_183337.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

Genes affected

RGS11 (HGNC:9993): (regulator of G protein signaling 11) The protein encoded by this gene belongs to the RGS (regulator of G protein signaling) family. Members of the RGS family act as GTPase-activating proteins on the alpha subunits of heterotrimeric, signal-transducing G proteins. This protein inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. Alternative splicing occurs at this locus and four transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Nov 2013]

FAM234A (HGNC:14163): (family with sequence similarity 234 member A) Located in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS11	NM_183337.3	c.1162G>A	p.Val388Ile	missense_variant	15/17	ENST00000397770.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS11	ENST00000397770.8	c.1162G>A	p.Val388Ile	missense_variant	15/17	1	NM_183337.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456686 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724196

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Nov 06, 2023

The c.1162G>A (p.V388I) alteration is located in exon 15 (coding exon 15) of the RGS11 gene. This alteration results from a G to A substitution at nucleotide position 1162, causing the valine (V) at amino acid position 388 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	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.57	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.045	D;D;D
Sift4G	Benign	0.091	T;T;D
Polyphen		1.0	D;.;P
Vest4		0.36
MutPred		0.49		Gain of helix (P = 0.2059);.;.;
MVP		0.53
MPC		0.089
ClinPred		0.82	D
GERP RS		3.6
Varity_R		0.23
gMVP		0.37

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: rs1374296910; hg19: chr16-320566;