NM_005873.3:c.28C>A

Variant names:

• chr20-64076859-G-T
• rs749086298
• NM_005873.3:c.28C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005873.3(RGS19):​c.28C>A​(p.Gln10Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,411,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: RGS19 NM_005873.3 missense, splice_region
• Scores: Splicing: ADA: 0.4479
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65
• Publications: 0 publications found

Genes affected

RGS19 (HGNC:13735): (regulator of G protein signaling 19) G proteins mediate a number of cellular processes. The protein encoded by this gene belongs to the RGS (regulators of G-protein signaling) family and specifically interacts with G protein, GAI3. This protein is a guanosine triphosphatase-activating protein that functions to down-regulate Galpha i/Galpha q-linked signaling. Alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. [provided by RefSeq, Jul 2008]

MIR6813 (HGNC:50017): (microRNA 6813) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27365416).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005873.3. 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
	RGS19	NM_005873.3	MANE Select	c.28C>A	p.Gln10Lys	missense splice_region	Exon 2 of 6	NP_005864.1	P49795
	RGS19	NM_001039467.2		c.28C>A	p.Gln10Lys	missense splice_region	Exon 2 of 6	NP_001034556.1	P49795
	MIR6813	NR_106871.1		n.*96C>A		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS19	ENST00000395042.2	TSL:1 MANE Select	c.28C>A	p.Gln10Lys	missense splice_region	Exon 2 of 6	ENSP00000378483.1	P49795
	RGS19	ENST00000332298.9	TSL:1	c.28C>A	p.Gln10Lys	missense splice_region	Exon 2 of 6	ENSP00000333194.5	P49795
	RGS19	ENST00000910389.1		c.28C>A	p.Gln10Lys	missense splice_region	Exon 2 of 6	ENSP00000580448.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000259 AC: 5 AN: 193068 AF XY: 0.0000470

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 9 AN: 1411138 Hom.: 0 Cov.: 31 AF XY: 0.00000713 AC XY: 5 AN XY: 700888

African (AFR) AF: 0.00 AC: 0 AN: 30192

American (AMR) AF: 0.00 AC: 0 AN: 30732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23536

East Asian (EAS) AF: 0.00 AC: 0 AN: 37924

South Asian (SAS) AF: 0.00 AC: 0 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4706

European-Non Finnish (NFE) AF: 0.00000731 AC: 8 AN: 1095034

Other (OTH) AF: 0.0000172 AC: 1 AN: 58066

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.094
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.27
Sift	Uncertain	0.027	D
Sift4G	Benign	0.22	T
Polyphen		0.93	P
Vest4		0.49
MutPred		0.16		Gain of ubiquitination at Q10 (P = 0.001)
MVP		0.78
MPC		1.5
ClinPred		0.30	T
GERP RS		3.6
Varity_R		0.096
gMVP		0.31
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.45
dbscSNV1_RF	Benign	0.54
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

Other links and lift over

dbSNP: rs749086298; hg19: chr20-62708212;