rs35254980

Positions:

• chr6-24848117-C-A
• chr6-24848117-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (123 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (99 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.994

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 -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 id 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/exons	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.1072G>T	p.Ala358Ser	missense_variant	12/22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1072G>T	p.Ala358Ser	missense_variant	12/22		NM_001286445.3	ENSP00000494268	A2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3235 AN: 152168 Hom.: 121 Cov.: 32

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

GnomAD3 exomes AF: 0.00593 AC: 1474 AN: 248672 Hom.: 30 AF XY: 0.00484 AC XY: 653 AN XY: 134922

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 SAS exome AF: 0.000197

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.: 99 Cov.: 31 AF XY: 0.00321 AC XY: 2331 AN XY: 726988

Gnomad4 AFR exome AF: 0.0752

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.00572

GnomAD4 genome AF: 0.0213 AC: 3242 AN: 152286 Hom.: 123 Cov.: 32 AF XY: 0.0197 AC XY: 1470 AN XY: 74482

Gnomad4 AFR AF: 0.0713

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00195

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00246 Hom.: 3

Bravo AF: 0.0242

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0642 AC: 255

ESP6500EA AF: 0.000958 AC: 8

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

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2017	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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.7
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	N
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	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
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	T
GERP RS		-3.5
Varity_R		0.021
gMVP		0.29

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

Other links and lift over

dbSNP: rs35254980; hg19: chr6-24848345;