rs35514577

Positions:

• chr6-24843299-C-T

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.1420G>A​(p.Glu474Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,614,014 control chromosomes in the GnomAD database, including 207 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 0.020 (106 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (101 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.22

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 6-24843299-C-T is Benign according to our data. Variant chr6-24843299-C-T is described in ClinVar as [Benign]. Clinvar id is 508611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.1420G>A	p.Glu474Lys	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.1420G>A	p.Glu474Lys	missense_variant	13/22		NM_001286445.3	ENSP00000494268	A2

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2998 AN: 152204 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00560 AC: 1394 AN: 249012 Hom.: 51 AF XY: 0.00404 AC XY: 546 AN XY: 135104

Gnomad AFR exome AF: 0.0681

Gnomad AMR exome AF: 0.00553

Gnomad ASJ exome AF: 0.00517

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00246 AC: 3591 AN: 1461692 Hom.: 101 Cov.: 32 AF XY: 0.00207 AC XY: 1506 AN XY: 727130

Gnomad4 AFR exome AF: 0.0681

Gnomad4 AMR exome AF: 0.00615

Gnomad4 ASJ exome AF: 0.00539

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000444

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.0198 AC: 3021 AN: 152322 Hom.: 106 Cov.: 32 AF XY: 0.0190 AC XY: 1413 AN XY: 74488

Gnomad4 AFR AF: 0.0663

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00407 Hom.: 29

Bravo AF: 0.0237

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0580 AC: 224

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.00635 AC: 767

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 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.Glu495Lys in exon 14 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 6.60% (647/9796) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs35514577). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.0060	T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	.;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	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.54	.;.;N;.;.;N;N;N;.;.;.;.;.
REVEL	Benign	0.039
Sift	Uncertain	0.016	.;.;D;.;.;D;D;D;.;.;.;.;.
Sift4G	Benign	0.90	.;T;T;.;.;T;T;T;.;.;.;.;.
Polyphen		0.0	B;B;B;.;.;B;B;.;B;B;.;.;.
Vest4		0.20, 0.20, 0.21, 0.20, 0.21
MVP		0.24
MPC		0.34
ClinPred		0.0084	T
GERP RS		3.3
Varity_R		0.043
gMVP		0.38

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: rs35514577; hg19: chr6-24843527; COSMIC: COSV99035584; COSMIC: COSV99035584;