20-64076859-G-T

Variant summary

Our verdict is Likely benign. Variant got -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. 14/23 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27365416).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS19	NM_005873.3	c.28C>A	p.Gln10Lys	missense_variant, splice_region_variant	2/6	ENST00000395042.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS19	ENST00000395042.2	c.28C>A	p.Gln10Lys	missense_variant, splice_region_variant	2/6	1	NM_005873.3	P1
RGS19	ENST00000332298.9	c.28C>A	p.Gln10Lys	missense_variant, splice_region_variant	2/6	1		P1
RGS19	ENST00000493165.1	n.614C>A		splice_region_variant, non_coding_transcript_exon_variant	2/4	3
RGS19	ENST00000479996.1	n.133-213C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000259 AC: 5 AN: 193068 Hom.: 0 AF XY: 0.0000470 AC XY: 5 AN XY: 106288

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 SAS 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

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: 0.00000731

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

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

Nov 18, 2023

The c.28C>A (p.Q10K) alteration is located in exon 2 (coding exon 1) of the RGS19 gene. This alteration results from a C to A substitution at nucleotide position 28, causing the glutamine (Q) at amino acid position 10 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	0.085
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.26	T;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;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.86	N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.22	T;T
Polyphen		0.93	P;P
Vest4		0.49
MutPred		0.16		Gain of ubiquitination at Q10 (P = 0.001);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs749086298; hg19: chr20-62708212;