20-64076859-G-A

Variant names:

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

Variant summary

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

The NM_005873.3(RGS19):​c.28C>T​(p.Gln10*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000032 in 1,563,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RGS19 NM_005873.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9907
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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>T	p.Gln10*	stop_gained splice_region	Exon 2 of 6	NP_005864.1	P49795
	RGS19	NM_001039467.2		c.28C>T	p.Gln10*	stop_gained splice_region	Exon 2 of 6	NP_001034556.1	P49795
	MIR6813	NR_106871.1		n.*96C>T		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>T	p.Gln10*	stop_gained splice_region	Exon 2 of 6	ENSP00000378483.1	P49795
	RGS19	ENST00000332298.9	TSL:1	c.28C>T	p.Gln10*	stop_gained splice_region	Exon 2 of 6	ENSP00000333194.5	P49795
	RGS19	ENST00000910389.1		c.28C>T	p.Gln10*	stop_gained splice_region	Exon 2 of 6	ENSP00000580448.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1411138 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 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: 0.00000365 AC: 4 AN: 1095034

Other (OTH) AF: 0.00 AC: 0 AN: 58066

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41424

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: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

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: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	55
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Benign	0.54	D
PhyloP100		2.7
Vest4		0.65
GERP RS		3.6
Mutation Taster		=19/180	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.71		Position offset: 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;