16-270786-C-T

Variant names:

• chr16-270786-C-T
• rs1198769877
• NM_183337.3:c.1025G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_183337.3(RGS11):​c.1025G>A​(p.Gly342Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G342V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: RGS11 NM_183337.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.89
• Publications: 0 publications found

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]

ENSG00000286901 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183337.3. 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
	RGS11	NM_183337.3	MANE Select	c.1025G>A	p.Gly342Glu	missense	Exon 14 of 17	NP_899180.1	O94810-1
	RGS11	NM_001286485.2		c.992G>A	p.Gly331Glu	missense	Exon 13 of 16	NP_001273414.1	O94810-2
	RGS11	NM_003834.3		c.962G>A	p.Gly321Glu	missense	Exon 14 of 17	NP_003825.1	O94810-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS11	ENST00000397770.8	TSL:1 MANE Select	c.1025G>A	p.Gly342Glu	missense	Exon 14 of 17	ENSP00000380876.3	O94810-1
	RGS11	ENST00000359740.6	TSL:1	c.992G>A	p.Gly331Glu	missense	Exon 13 of 16	ENSP00000352778.5	O94810-2
	RGS11	ENST00000316163.9	TSL:1	c.962G>A	p.Gly321Glu	missense	Exon 14 of 17	ENSP00000319069.5	O94810-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.57	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.36		Gain of solvent accessibility (P = 0.0596)
MVP		0.71
MPC		0.58
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.70
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1198769877; hg19: chr16-320785;