rs35780910

Positions:

• chr6-24843224-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286445.3(RIPOR2):​c.1495C>T​(p.Arg499Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,968 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (151 hom., cov: 32)
  • Exomes 𝑓: 0.013 (283 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.28

Genes affected

RIPOR2 (HGNC:13872): (RHO family interacting cell polarization regulator 2) This gene encodes an atypical inhibitor of the small G protein RhoA. Inhibition of RhoA activity by the encoded protein mediates myoblast fusion and polarization of T cells and neutrophils. The encoded protein is a component of hair cell stereocilia that is essential for hearing. A splice site mutation in this gene results in hearing loss in human patients. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018260479).
• BP6: Variant 6-24843224-G-A is Benign according to our data. Variant chr6-24843224-G-A is described in ClinVar as [Benign]. Clinvar id is 508153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.1495C>T	p.Arg499Cys	missense_variant	13/22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1495C>T	p.Arg499Cys	missense_variant	13/22		NM_001286445.3	ENSP00000494268	A2

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4671 AN: 152148 Hom.: 151 Cov.: 32

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0137 AC: 3419 AN: 248946 Hom.: 100 AF XY: 0.0119 AC XY: 1609 AN XY: 135034

Gnomad AFR exome AF: 0.0858

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0127 AC: 18582 AN: 1461702 Hom.: 283 Cov.: 32 AF XY: 0.0120 AC XY: 8731 AN XY: 727136

Gnomad4 AFR exome AF: 0.0852

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00285

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0307 AC: 4674 AN: 152266 Hom.: 151 Cov.: 32 AF XY: 0.0297 AC XY: 2215 AN XY: 74460

Gnomad4 AFR AF: 0.0823

Gnomad4 AMR AF: 0.0248

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00992

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0136 Hom.: 60

Bravo AF: 0.0359

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.0810 AC: 309

ESP6500EA AF: 0.0114 AC: 94

ExAC AF: 0.0144 AC: 1737

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0120

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Arg520Cys in exon 14 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 8.65% (848/9800) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs35780910). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.0028	T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;.;D;D;.;D;D;.;D;D;.;D
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.65	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.51	.;.;N;.;.;N;N;N;.;.;.;.;.
REVEL	Benign	0.061
Sift	Uncertain	0.020	.;.;D;.;.;D;D;D;.;.;.;.;.
Sift4G	Uncertain	0.052	.;T;T;.;.;T;T;T;.;.;.;.;.
Polyphen		0.0020	B;B;B;.;.;D;B;.;D;D;.;.;.
Vest4		0.12, 0.14, 0.25, 0.24, 0.24
MPC		0.92
ClinPred		0.023	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.26

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: rs35780910; hg19: chr6-24843452;