6-24806425-T-A

Variant names:

• chr6-24806425-T-A
• rs368088673
• NM_001286445.3:c.3092A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001286445.3(RIPOR2):​c.3092A>T​(p.Asp1031Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1031G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00
• Publications: 0 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):

• nonsyndromic genetic hearing loss

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 21

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 104

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000282804 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31172687).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	NM_001286445.3	MANE Select	c.3092A>T	p.Asp1031Val	missense	Exon 22 of 22	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.3155A>T	p.Asp1052Val	missense	Exon 23 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.3005A>T	p.Asp1002Val	missense	Exon 22 of 22	NP_001332960.1	F5GX51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.3092A>T	p.Asp1031Val	missense	Exon 22 of 22	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.3155A>T	p.Asp1052Val	missense	Exon 23 of 23	ENSP00000259698.4	Q9Y4F9-1
	ENSG00000282804	ENST00000562221.1	TSL:5	c.131A>T	p.Asp44Val	missense	Exon 2 of 3	ENSP00000455145.1	H3BP45

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399510 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690258

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49372

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078968

Other (OTH) AF: 0.00 AC: 0 AN: 58080

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.46	T
PhyloP100		5.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.30
MutPred		0.34		Gain of sheet (P = 0.0016)
MVP		0.56
MPC		1.1
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.20
gMVP		0.28
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs368088673; hg19: chr6-24806653;