rs143785002

Positions:

• chr6-24842946-T-G

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.1773A>C​(p.Leu591Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,525,798 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 0.0037 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00070 (3 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.17

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=0.004411757).
• BP6: Variant 6-24842946-T-G is Benign according to our data. Variant chr6-24842946-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 446060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.1773A>C	p.Leu591Phe	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.1773A>C	p.Leu591Phe	missense_variant	13/22		NM_001286445.3	ENSP00000494268	A2

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152178 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

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: 0.000309

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00173 AC: 315 AN: 181940 Hom.: 3 AF XY: 0.00138 AC XY: 133 AN XY: 96292

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000639

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.000725

GnomAD4 exome AF: 0.000700 AC: 961 AN: 1373502 Hom.: 3 Cov.: 32 AF XY: 0.000662 AC XY: 446 AN XY: 673820

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000377

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152296 Hom.: 2 Cov.: 31 AF XY: 0.00365 AC XY: 272 AN XY: 74476

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00101 Hom.: 2

Bravo AF: 0.00447

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0141 AC: 53

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.00161 AC: 194

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Leu612Phe in exon 14 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 1.57% (151/9612) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs143785002). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0028	T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.11	.;T;.;T;T;.;T;T;.;T;T;.;T
MetaRNN	Benign	0.0044	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.61	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.98	.;.;N;N;.;N;N;N;.;.;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.49	.;.;T;T;.;T;T;T;.;.;.;.;.
Sift4G	Benign	0.50	.;T;T;.;.;T;T;T;.;.;.;.;.
Polyphen		0.0	B;B;B;.;.;B;B;.;B;B;.;.;.
Vest4		0.13, 0.11, 0.15, 0.15
MutPred		0.31		Loss of disorder (P = 0.1734);Loss of disorder (P = 0.1734);Loss of disorder (P = 0.1734);.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.1734);
MVP		0.043
MPC		0.33
ClinPred		0.011	T
GERP RS		4.6
Varity_R		0.055
gMVP		0.11

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: rs143785002; hg19: chr6-24843174;