4-3316226-G-A

Position:

• chr4-3316226-G-A

Variant summary

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

The NM_001394154.1(RGS12):​c.56G>A​(p.Arg19Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,384 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RGS12 NM_001394154.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59

Genes affected

RGS12 (HGNC:9994): (regulator of G protein signaling 12) This gene encodes a member of the 'regulator of G protein signaling' (RGS) gene family. The encoded protein may function as a guanosine triphosphatase (GTPase)-activating protein as well as a transcriptional repressor. This protein may play a role in tumorigenesis. Multiple transcript variants encoding distinct isoforms have been identified for this gene. Other alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

RGS12 (HGNC:):

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	Protein	UniProt
RGS12	NM_001394154.1	c.56G>A	p.Arg19Lys	missense_variant	2/18	ENST00000336727.8	NP_001381083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS12	ENST00000336727.8	c.56G>A	p.Arg19Lys	missense_variant	2/18	1	NM_001394154.1	ENSP00000338509.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456384 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723494

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: 9.02e-7

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

Oct 16, 2024

The c.56G>A (p.R19K) alteration is located in exon 2 (coding exon 1) of the RGS12 gene. This alteration results from a G to A substitution at nucleotide position 56, causing the arginine (R) at amino acid position 19 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	.;T;T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.046	D;T;T
Sift4G	Uncertain	0.055	T;D;T
Polyphen		0.98	D;D;D
Vest4		0.46
MutPred		0.32		Gain of methylation at R19 (P = 0.0127);Gain of methylation at R19 (P = 0.0127);Gain of methylation at R19 (P = 0.0127);
MVP		0.67
MPC		0.65
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.14
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs1724731759; hg19: chr4-3317953;