rs35254980

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001286445.3(RIPOR2):c.1072G>T(p.Ala358Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,613,742 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A358T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.021 ( 123 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 99 hom. )

Consequence

RIPOR2
NM_001286445.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.994

Publications

2 publications found

Variant links:

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]

RIPOR2 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 104
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nonsyndromic hearing loss 21
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RIPOR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013438761).

BP6

Variant 6-24848117-C-A is Benign according to our data. Variant chr6-24848117-C-A is described in ClinVar as Benign. ClinVar VariationId is 509123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPOR2	NM_001286445.3 link	c.1072G>T	p.Ala358Ser	missense_variant	Exon 12 of 22	ENST00000643898.2	NP_001273374.1	A0A2R8YEE0B7Z5J9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2 link	c.1072G>T	p.Ala358Ser	missense_variant	Exon 12 of 22		NM_001286445.3	ENSP00000494268.2		A0A2R8YEE0

Frequencies

GnomAD3 genomes

AF:

0.0213

AC:

3235

AN:

152168

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0714

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00195

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.00593

AC:

1474

AN:

248672

AF XY:

0.00484

show subpopulations

Gnomad AFR exome

AF:

0.0713

Gnomad AMR exome

AF:

0.00467

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00356

AC:

5198

AN:

1461456

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

2331

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.0752

AC:

2516

AN:

33470

American (AMR)

AF:

0.00481

AC:

215

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39662

South Asian (SAS)

AF:

0.000162

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00183

AC:

2039

AN:

1111774

Other (OTH)

AF:

0.00572

AC:

345

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

253

506

758

1011

1264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0213

AC:

3242

AN:

152286

Hom.:

123

Cov.:

AF XY:

0.0197

AC XY:

1470

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0713

AC:

2963

AN:

41542

American (AMR)

AF:

0.00706

AC:

108

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00195

AC:

133

AN:

68036

Other (OTH)

AF:

0.0161

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

154

307

461

614

768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00704

Hom.:

Bravo

AF:

0.0242

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.0642

AC:

255

ESP6500EA

AF:

0.000958

AC:

ExAC

AF:

0.00702

AC:

849

EpiCase

AF:

0.00175

EpiControl

AF:

0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala329Ser in exon 12 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 7.49% (699/9338) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs35254980). -

Oct 23, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.7

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0010

T;T;T;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.86

.;D;.;D;D;.;D;D;.;D;D;.;D

MetaRNN

Benign

0.0013

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

0.99

PrimateAI

Benign

0.26

PROVEAN

Benign

1.3

.;.;N;.;.;N;N;N;.;.;.;.;.

REVEL

Benign

0.043

Sift

Benign

0.56

.;.;T;.;.;T;T;T;.;.;.;.;.

Sift4G

Benign

0.51

.;T;T;.;.;T;T;T;.;.;.;.;.

Polyphen

0.027

B;B;B;.;.;B;B;.;B;B;.;.;.

Vest4

0.26, 0.25, 0.28, 0.28, 0.29

MVP

0.093

MPC

0.31

ClinPred

0.0021

GERP RS

-3.5

Varity_R

0.021

gMVP

0.29

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over