19-32676628-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207391.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS9BP	NM_207391.3	MANE Select	c.365C>T	p.Ser122Phe	missense	Exon 1 of 1	NP_997274.2	Q6ZS82

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS9BP	ENST00000334176.4	TSL:6 MANE Select	c.365C>T	p.Ser122Phe	missense	Exon 1 of 1	ENSP00000334134.3	Q6ZS82
	ANKRD27	ENST00000590519.2	TSL:5	c.-873G>A		upstream_gene	N/A	ENSP00000464819.1	K7EIN0

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000321 AC: 1 AN: 31174

American (AMR) AF: 0.00 AC: 0 AN: 35464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24972

East Asian (EAS) AF: 0.00 AC: 0 AN: 35490

South Asian (SAS) AF: 0.00 AC: 0 AN: 78824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076250

Other (OTH) AF: 0.00 AC: 0 AN: 57594

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000121 AC: 5 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.3
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
PromoterAI		-0.0043	Neutral
Varity_R		0.17
gMVP		0.61
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs749927570; hg19: chr19-33167534;