NM_001286445.3:c.1045G>A

Variant names:

• chr6-24848144-C-T
• rs35331811
• NM_001286445.3:c.1045G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001286445.3(RIPOR2):​c.1045G>A​(p.Val349Met) variant causes a missense change. The variant allele was found at a frequency of 0.00901 in 1,613,324 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (117 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.74
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 104

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss 21

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045339167).
• BP6: Variant 6-24848144-C-T is Benign according to our data. Variant chr6-24848144-C-T is described in ClinVar as Benign. ClinVar VariationId is 508603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00925 (1409/152280) while in subpopulation AMR AF = 0.0347 (531/15286). AF 95% confidence interval is 0.0323. There are 13 homozygotes in GnomAd4. There are 727 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286445.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	NM_001286445.3	MANE Select	c.1045G>A	p.Val349Met	missense	Exon 12 of 22	NP_001273374.1
	RIPOR2	NM_014722.5		c.958G>A	p.Val320Met	missense	Exon 12 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.958G>A	p.Val320Met	missense	Exon 12 of 22	NP_001332960.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.1045G>A	p.Val349Met	missense	Exon 12 of 22	ENSP00000494268.2
	RIPOR2	ENST00000259698.9	TSL:1	c.958G>A	p.Val320Met	missense	Exon 12 of 23	ENSP00000259698.4
	RIPOR2	ENST00000378023.8	TSL:1	c.958G>A	p.Val320Met	missense	Exon 12 of 14	ENSP00000367262.4

Frequencies

GnomAD3 genomes AF: 0.00925 AC: 1408 AN: 152162 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0165

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00683

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.0131 AC: 3242 AN: 247722 AF XY: 0.0113

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.0464

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.0178

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00899 AC: 13134 AN: 1461044 Hom.: 117 Cov.: 31 AF XY: 0.00872 AC XY: 6337 AN XY: 726748

African (AFR) AF: 0.00138 AC: 46 AN: 33452

American (AMR) AF: 0.0434 AC: 1938 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.000958 AC: 25 AN: 26104

East Asian (EAS) AF: 0.0177 AC: 701 AN: 39654

South Asian (SAS) AF: 0.00430 AC: 370 AN: 86104

European-Finnish (FIN) AF: 0.0150 AC: 803 AN: 53376

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.00797 AC: 8863 AN: 1111618

Other (OTH) AF: 0.00633 AC: 382 AN: 60364

GnomAD4 genome AF: 0.00925 AC: 1409 AN: 152280 Hom.: 13 Cov.: 32 AF XY: 0.00976 AC XY: 727 AN XY: 74466

African (AFR) AF: 0.00202 AC: 84 AN: 41542

American (AMR) AF: 0.0347 AC: 531 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0166 AC: 86 AN: 5190

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4830

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00684 AC: 465 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00787 Hom.: 35

Bravo AF: 0.0104

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000755 AC: 3

ESP6500EA AF: 0.00742 AC: 62

ExAC AF: 0.0110 AC: 1326

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val320Met in exon 12 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 5.24% (567/10816) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs35331811).

Oct 25, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 09, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0045	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.29
Sift	Benign	0.042	D
Sift4G	Benign	0.097	T
Polyphen		1.0	D
Vest4		0.34
MPC		0.99
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.070
gMVP		0.51
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35331811; hg19: chr6-24848372; COSMIC: COSV52427859;