6-24806384-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001286445.3(RIPOR2):c.3133A>G(p.Thr1045Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000299 in 1,549,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.00

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0100573).
• BP6: Variant 6-24806384-T-C is Benign according to our data. Variant chr6-24806384-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 595299.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPOR2	NM_001286445.3	c.3133A>G	p.Thr1045Ala	missense_variant	22/22	ENST00000643898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPOR2	ENST00000643898.2	c.3133A>G	p.Thr1045Ala	missense_variant	22/22		NM_001286445.3	A2
RIPOR2	ENST00000259698.9	c.3196A>G	p.Thr1066Ala	missense_variant	23/23	1		A2
RIPOR2	ENST00000613507.4	c.3196A>G	p.Thr1066Ala	missense_variant	23/23	5		A2
RIPOR2	ENST00000538035.6	c.3046A>G	p.Thr1016Ala	missense_variant	22/22	2		A2

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000333 AC: 52 AN: 156216 Hom.: 0 AF XY: 0.000242 AC XY: 20 AN XY: 82758

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.000246

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: 0.000229

GnomAD4 exome AF: 0.000164 AC: 229 AN: 1397596 Hom.: 1 Cov.: 31 AF XY: 0.000135 AC XY: 93 AN XY: 689468

Gnomad4 AFR exome AF: 0.00612

Gnomad4 AMR exome AF: 0.000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.000293

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74484

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000777 Hom.: 0

Bravo AF: 0.00185

ESP6500AA AF: 0.00434 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000638 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 23, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Thr1066Ala in exon 23 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 0.65% (14/2154) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs373913240). -

RIPOR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;.;T;.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.1	D;.;.;D;.;.
Sift	Pathogenic	0.0	D;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;.;D;D;.;.
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.69, 0.69
MVP		0.77
MPC		1.0
ClinPred		0.082	T
GERP RS		4.9
Varity_R		0.55
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs373913240; hg19: chr6-24806612;