rs142889670

chr6-24843106-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001286445.3(RIPOR2):c.1613C>T(p.Ser538Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,964 control chromosomes in the GnomAD database, including 5 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (3 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.39

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030991137).
• BP6: Variant 6-24843106-G-A is Benign according to our data. Variant chr6-24843106-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPOR2	NM_001286445.3	c.1613C>T	p.Ser538Leu	missense_variant	13/22	ENST00000643898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1613C>T	p.Ser538Leu	missense_variant	13/22		NM_001286445.3	A2

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 570 AN: 152148 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00146 AC: 363 AN: 248878 Hom.: 3 AF XY: 0.00108 AC XY: 146 AN XY: 134986

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000728 AC: 1064 AN: 1461698 Hom.: 3 Cov.: 32 AF XY: 0.000673 AC XY: 489 AN XY: 727134

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000383

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00378 AC: 575 AN: 152266 Hom.: 2 Cov.: 31 AF XY: 0.00369 AC XY: 275 AN XY: 74452

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.0228 Hom.: 2353

Bravo AF: 0.00452

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0137 AC: 55

ESP6500EA AF: 0.000478 AC: 4

ExAC AF: 0.00164 AC: 198

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Ser559Leu in exon 14 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 1.56% (153/9798) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs142889670). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	7.4
Dann	Benign	0.47
DEOGEN2	Benign	0.0040	T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.027	N
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
Polyphen		0.0	B;B;B;.;.;B;B;.;B;B;.;.;.
Vest4		0.047, 0.052, 0.068, 0.073, 0.070
MVP		0.043
MPC		0.27
ClinPred		0.0016	T
GERP RS		4.4
Varity_R		0.025
gMVP		0.14

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: rs142889670; hg19: chr6-24843334; COSMIC: COSV52423869;