19-32676628-C-T

Variant names:

• chr19-32676628-C-T
• rs749927570
• NM_207391.3:c.365C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_207391.3(RGS9BP):​c.365C>T​(p.Ser122Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000392 in 1,530,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S122C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RGS9BP NM_207391.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29

Genes affected

RGS9BP (HGNC:30304): (regulator of G protein signaling 9 binding protein) The protein encoded by this gene functions as a regulator of G protein-coupled receptor signaling in phototransduction. Studies in bovine and mouse show that this gene is expressed only in the retina, and is localized in the rod outer segment membranes. This protein is associated with a heterotetrameric complex, specifically interacting with the regulator of G-protein signaling 9, and appears to function as the membrane anchor for the other largely soluble interacting partners. Mutations in this gene are associated with prolonged electroretinal response suppression (PERRS), also known as bradyopsia. [provided by RefSeq, Mar 2010]

ANKRD27 (HGNC:25310): (ankyrin repeat domain 27) Enables guanyl-nucleotide exchange factor activity and small GTPase binding activity. Involved in endocytic recycling and negative regulation of SNARE complex assembly. Acts upstream of or within early endosome to late endosome transport. Located in endosome; lysosome; and plasma membrane. Implicated in eosinophilic esophagitis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27651542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS9BP	NM_207391.3	c.365C>T	p.Ser122Phe	missense_variant	Exon 1 of 1	ENST00000334176.4	NP_997274.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS9BP	ENST00000334176.4	c.365C>T	p.Ser122Phe	missense_variant	Exon 1 of 1	6	NM_207391.3	ENSP00000334134.3
ANKRD27	ENST00000590519.2	c.-873G>A		upstream_gene_variant		5		ENSP00000464819.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151994 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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 AF: 7.25e-7 AC: 1 AN: 1378492 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 679748

Gnomad4 AFR exome AF: 0.0000321

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151994 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74234

Gnomad4 AFR AF: 0.000121

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.85	P
Vest4		0.14
MutPred		0.42		Loss of glycosylation at S122 (P = 0.003);
MVP		0.75
ClinPred		0.87	D
GERP RS		2.5
Varity_R		0.17
gMVP		0.61

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: rs749927570; hg19: chr19-33167534;