Variant 6-24809779-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001286445.3(RIPOR2):c.2981C>T(p.Thr994Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,550,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RIPOR2
NM_001286445.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.625

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026141971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPOR2	NM_001286445.3 linkuse as main transcript	c.2981C>T	p.Thr994Ile	missense_variant	21/22	ENST00000643898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPOR2	ENST00000643898.2 linkuse as main transcript	c.2981C>T	p.Thr994Ile	missense_variant	21/22		NM_001286445.3	A2
RIPOR2	ENST00000259698.9 linkuse as main transcript	c.3044C>T	p.Thr1015Ile	missense_variant	22/23	1		A2	Q9Y4F9-1
RIPOR2	ENST00000613507.4 linkuse as main transcript	c.3044C>T	p.Thr1015Ile	missense_variant	22/23	5		A2	Q9Y4F9-1
RIPOR2	ENST00000538035.6 linkuse as main transcript	c.2894C>T	p.Thr965Ile	missense_variant	21/22	2		A2

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000447

AC:

AN:

156472

Hom.:

AF XY:

0.0000362

AC XY:

AN XY:

82926

show subpopulations

Gnomad AFR exome

AF:

0.000884

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1398264

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

689692

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0000280

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:

0.0000518

GnomAD4 genome

AF:

0.000184

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.00289

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.3044C>T (p.T1015I) alteration is located in exon 22 (coding exon 21) of the FAM65B gene. This alteration results from a C to T substitution at nucleotide position 3044, causing the threonine (T) at amino acid position 1015 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.53

T;.;T;.;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.026

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.89

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.5

N;.;.;N;.;.

Sift

Benign

0.067

T;.;.;T;.;.

Sift4G

Uncertain

0.0080

D;.;T;T;.;.

Polyphen

0.63

.;P;P;P;.;.

Vest4

0.38

MVP

0.64

MPC

0.33

ClinPred

0.25

GERP RS

2.1

Varity_R

0.039

gMVP

0.096

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over