1-163161917-T-C

Variant names:

• chr1-163161917-T-C
• rs1044247757
• NM_003617.4:c.215A>G

Variant summary

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

The NM_003617.4(RGS5):​c.215A>G​(p.Asn72Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RGS5 NM_003617.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004686
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.362

Genes affected

RGS5 (HGNC:10001): (regulator of G protein signaling 5) This locus represents naturally occurring readthrough transcription between the neighboring LOC127814295 (uncharacterized LOC127814295) and RGS5 (regulator of G-protein signaling 5) genes on chromosome 1. Some variants of the readthrough transcript encode novel proteins with unique N-termini. [provided by RefSeq, Nov 2022]

RGS5-AS1 (HGNC:40504): (RGS5 antisense RNA 1)

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=0.089766085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS5	NM_003617.4	c.215A>G	p.Asn72Ser	missense_variant, splice_region_variant	Exon 3 of 5	ENST00000313961.10	NP_003608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS5	ENST00000313961.10	c.215A>G	p.Asn72Ser	missense_variant, splice_region_variant	Exon 3 of 5	1	NM_003617.4	ENSP00000319308.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215A>G (p.N72S) alteration is located in exon 3 (coding exon 3) of the RGS5 gene. This alteration results from a A to G substitution at nucleotide position 215, causing the asparagine (N) at amino acid position 72 to be replaced by a serine (S). 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	0.054
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.090	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.7	N;.;N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.060	N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.15	T;T;T;.
Polyphen		0.0	B;.;.;.
Vest4		0.096
MutPred		0.34		Loss of catalytic residue at N72 (P = 0.0553);.;Loss of catalytic residue at N72 (P = 0.0553);.;
MVP		0.21
MPC		0.14
ClinPred		0.16	T
GERP RS		1.5
Varity_R		0.037
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.010		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: rs1044247757; hg19: chr1-163131707;