rs16896629

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152732.5(RSPH9):c.781G>A(p.Val261Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 1,614,136 control chromosomes in the GnomAD database, including 4,504 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 440 hom., cov: 33)

Exomes 𝑓: 0.061 ( 4064 hom. )

Consequence

RSPH9
NM_152732.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.07

Publications

26 publications found

Variant links:

Genes affected

RSPH9 (HGNC:21057): (radial spoke head component 9) This gene encodes a protein thought to be a component of the radial spoke head in motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia 12. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jul 2010]

RSPH9 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 12
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=9.112358E-4).

BP6

Variant 6-43670899-G-A is Benign according to our data. Variant chr6-43670899-G-A is described in ClinVar as Benign. ClinVar VariationId is 165065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH9	NM_152732.5 link	c.781G>A	p.Val261Ile	missense_variant	Exon 5 of 5	ENST00000372163.5	NP_689945.2	Q9H1X1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH9	ENST00000372163.5 link	c.781G>A	p.Val261Ile	missense_variant	Exon 5 of 5	1	NM_152732.5	ENSP00000361236.4		Q9H1X1-1
RSPH9	ENST00000372165.8 link	c.833G>A	p.Arg278His	missense_variant	Exon 6 of 6	2		ENSP00000361238.4		Q9H1X1-2

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10068

AN:

152204

Hom.:

443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0747

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0630

Gnomad ASJ

AF:

0.0691

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.0307

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0501

Gnomad OTH

AF:

0.0707

GnomAD2 exomes

AF:

0.0766

AC:

19260

AN:

251432

AF XY:

0.0801

show subpopulations

Gnomad AFR exome

AF:

0.0771

Gnomad AMR exome

AF:

0.0573

Gnomad ASJ exome

AF:

0.0706

Gnomad EAS exome

AF:

0.190

Gnomad FIN exome

AF:

0.0304

Gnomad NFE exome

AF:

0.0514

Gnomad OTH exome

AF:

0.0668

GnomAD4 exome

AF:

0.0610

AC:

89175

AN:

1461814

Hom.:

4064

Cov.:

AF XY:

0.0642

AC XY:

46666

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.0764

AC:

2558

AN:

33480

American (AMR)

AF:

0.0583

AC:

2609

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0706

AC:

1844

AN:

26136

East Asian (EAS)

AF:

0.218

AC:

8671

AN:

39700

South Asian (SAS)

AF:

0.154

AC:

13278

AN:

86258

European-Finnish (FIN)

AF:

0.0308

AC:

1647

AN:

53406

Middle Eastern (MID)

AF:

0.0938

AC:

541

AN:

5768

European-Non Finnish (NFE)

AF:

0.0482

AC:

53647

AN:

1111950

Other (OTH)

AF:

0.0725

AC:

4380

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

4693

9386

14078

18771

23464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2188

4376

6564

8752

10940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0661

AC:

10074

AN:

152322

Hom.:

440

Cov.:

AF XY:

0.0673

AC XY:

5013

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0746

AC:

3101

AN:

41576

American (AMR)

AF:

0.0630

AC:

964

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0691

AC:

240

AN:

3472

East Asian (EAS)

AF:

0.208

AC:

1075

AN:

5176

South Asian (SAS)

AF:

0.160

AC:

771

AN:

4828

European-Finnish (FIN)

AF:

0.0307

AC:

326

AN:

10620

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0501

AC:

3409

AN:

68022

Other (OTH)

AF:

0.0690

AC:

146

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

499

999

1498

1998

2497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0584

Hom.:

561

Bravo

AF:

0.0673

TwinsUK

AF:

0.0510

AC:

189

ALSPAC

AF:

0.0410

AC:

158

ESP6500AA

AF:

0.0808

AC:

356

ESP6500EA

AF:

0.0542

AC:

466

ExAC

AF:

0.0796

AC:

9671

Asia WGS

AF:

0.168

AC:

583

AN:

3478

EpiCase

AF:

0.0558

EpiControl

AF:

0.0581

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg278His in exon 6 of RSPH9: This variant is not expected to have clinical sign ificance because it has been identified in 8.1% (356/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs16896629). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Dec 12, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 05, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 12

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.77

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.25

MetaRNN

Benign

0.00091

MetaSVM

Benign

-0.92

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

0.26

REVEL

Benign

0.036

Sift

Benign

0.61

Sift4G

Benign

0.26

Vest4

0.025

MPC

0.060

ClinPred

0.017

GERP RS

3.4

Varity_R

0.041

gMVP

0.12

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over