6-153026517-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012419.5(RGS17):c.146G>C(p.Gly49Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RGS17 NM_012419.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

RGS17 (HGNC:14088): (regulator of G protein signaling 17) This gene encodes a member of the regulator of G-protein signaling family. This protein contains a conserved, 120 amino acid motif called the RGS domain and a cysteine-rich region. The protein attenuates the signaling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein (GAP), increasing the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16213307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS17	NM_012419.5	c.146G>C	p.Gly49Ala	missense_variant	3/5	ENST00000206262.2
RGS17	XM_047418634.1	c.191G>C	p.Gly64Ala	missense_variant	3/5
RGS17	XM_047418635.1	c.179G>C	p.Gly60Ala	missense_variant	3/5
RGS17	XM_047418636.1	c.146G>C	p.Gly49Ala	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS17	ENST00000206262.2	c.146G>C	p.Gly49Ala	missense_variant	3/5	1	NM_012419.5	P1
RGS17	ENST00000367225.6	c.146G>C	p.Gly49Ala	missense_variant	2/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460974 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726830

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 22, 2022

The c.146G>C (p.G49A) alteration is located in exon 3 (coding exon 2) of the RGS17 gene. This alteration results from a G to C substitution at nucleotide position 146, causing the glycine (G) at amino acid position 49 to be replaced by an alanine (A). 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	0.090
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Benign	0.85
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.067
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.32	T;T
Polyphen		0.0	B;B
Vest4		0.30
MutPred		0.26		Gain of methylation at R54 (P = 0.1146);Gain of methylation at R54 (P = 0.1146);
MVP		0.47
MPC		0.42
ClinPred		0.071	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-153347652;