6-153024447-T-C

Variant summary

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

The NM_012419.5(RGS17):c.259A>G(p.Lys87Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: RGS17 NM_012419.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

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=0.13298205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS17	NM_012419.5	c.259A>G	p.Lys87Glu	missense_variant	4/5	ENST00000206262.2
RGS17	XM_047418634.1	c.304A>G	p.Lys102Glu	missense_variant	4/5
RGS17	XM_047418635.1	c.292A>G	p.Lys98Glu	missense_variant	4/5
RGS17	XM_047418636.1	c.259A>G	p.Lys87Glu	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS17	ENST00000206262.2	c.259A>G	p.Lys87Glu	missense_variant	4/5	1	NM_012419.5	P1
RGS17	ENST00000367225.6	c.259A>G	p.Lys87Glu	missense_variant	3/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000314 AC: 79 AN: 251342 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000625

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000430 AC: 628 AN: 1461854 Hom.: 1 Cov.: 32 AF XY: 0.000477 AC XY: 347 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000526

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74504

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000446 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.00115

EpiControl AF: 0.000415

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

Sep 14, 2022

The c.259A>G (p.K87E) alteration is located in exon 4 (coding exon 3) of the RGS17 gene. This alteration results from a A to G substitution at nucleotide position 259, causing the lysine (K) at amino acid position 87 to be replaced by a glutamic acid (E). 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	0.24
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.22
Sift	Benign	0.033	D;D
Sift4G	Benign	0.071	T;T
Polyphen		0.11	B;B
Vest4		0.58
MVP		0.43
MPC		0.69
ClinPred		0.11	T
GERP RS		6.0
Varity_R		0.87
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs151215161; hg19: chr6-153345582; COSMIC: COSV99057339;