rs739999

Variant names:

• chr16-269512-A-G
• rs739999
• NM_183337.3:c.1280T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_183337.3(RGS11):​c.1280T>C​(p.Met427Thr) variant causes a missense change. The variant allele was found at a frequency of 0.125 in 1,612,686 control chromosomes in the GnomAD database, including 23,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (7803 hom., cov: 34)
  • Exomes 𝑓: 0.11 (15857 hom.)
• Consequence: RGS11 NM_183337.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.41
• Publications: 33 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]

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

ENSG00000286901 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5902107E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS11	NM_183337.3	MANE Select	c.1280T>C	p.Met427Thr	missense	Exon 16 of 17	NP_899180.1
	RGS11	NM_001286485.2		c.1247T>C	p.Met416Thr	missense	Exon 15 of 16	NP_001273414.1
	RGS11	NM_003834.3		c.1217T>C	p.Met406Thr	missense	Exon 16 of 17	NP_003825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS11	ENST00000397770.8	TSL:1 MANE Select	c.1280T>C	p.Met427Thr	missense	Exon 16 of 17	ENSP00000380876.3
	RGS11	ENST00000359740.6	TSL:1	c.1247T>C	p.Met416Thr	missense	Exon 15 of 16	ENSP00000352778.5
	RGS11	ENST00000316163.9	TSL:1	c.1217T>C	p.Met406Thr	missense	Exon 16 of 17	ENSP00000319069.5

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36703 AN: 152116 Hom.: 7762 Cov.: 34

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0550

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0864

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.173 AC: 43253 AN: 250050 AF XY: 0.156

Gnomad AFR exome AF: 0.580

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.324

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.0858

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.113 AC: 164345 AN: 1460452 Hom.: 15857 Cov.: 31 AF XY: 0.111 AC XY: 80395 AN XY: 726572

African (AFR) AF: 0.579 AC: 19386 AN: 33458

American (AMR) AF: 0.292 AC: 13056 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5398 AN: 26104

East Asian (EAS) AF: 0.299 AC: 11849 AN: 39680

South Asian (SAS) AF: 0.122 AC: 10492 AN: 86246

European-Finnish (FIN) AF: 0.0526 AC: 2765 AN: 52542

Middle Eastern (MID) AF: 0.185 AC: 1064 AN: 5766

European-Non Finnish (NFE) AF: 0.0822 AC: 91384 AN: 1111622

Other (OTH) AF: 0.148 AC: 8951 AN: 60356

GnomAD4 genome AF: 0.242 AC: 36793 AN: 152234 Hom.: 7803 Cov.: 34 AF XY: 0.237 AC XY: 17677 AN XY: 74450

African (AFR) AF: 0.564 AC: 23419 AN: 41536

American (AMR) AF: 0.219 AC: 3355 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 678 AN: 3472

East Asian (EAS) AF: 0.323 AC: 1666 AN: 5164

South Asian (SAS) AF: 0.123 AC: 595 AN: 4830

European-Finnish (FIN) AF: 0.0550 AC: 584 AN: 10624

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0864 AC: 5876 AN: 68002

Other (OTH) AF: 0.213 AC: 449 AN: 2108

Alfa AF: 0.143 Hom.: 11905

Bravo AF: 0.275

TwinsUK AF: 0.0717 AC: 266

ALSPAC AF: 0.0848 AC: 327

ESP6500AA AF: 0.550 AC: 2422

ESP6500EA AF: 0.0894 AC: 769

ExAC AF: 0.174 AC: 21133

Asia WGS AF: 0.220 AC: 762 AN: 3478

EpiCase AF: 0.0954

EpiControl AF: 0.0981

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.1
DANN	Benign	0.55
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.000016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.2	N
PhyloP100		4.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.11
ClinPred		0.0024	T
GERP RS		3.5
Varity_R		0.023
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs739999; hg19: chr16-319511; COSMIC: COSV51451743; COSMIC: COSV51451743;