dbSNP rs368519003: RSPH9:p.Arg139Cys (chr6-43655583-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_152732.5(RSPH9):c.415C>T(p.Arg139Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

RSPH9
NM_152732.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.75

Publications

1 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: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152732.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RSPH9	NM_152732.5	MANE Select	c.415C>T	p.Arg139Cys	missense	Exon 3 of 5	NP_689945.2
RSPH9	NM_001424119.1		c.415C>T	p.Arg139Cys	missense	Exon 3 of 6	NP_001411048.1
RSPH9	NM_001424121.1		c.415C>T	p.Arg139Cys	missense	Exon 3 of 4	NP_001411050.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPH9	ENST00000372163.5	TSL:1 MANE Select	c.415C>T	p.Arg139Cys	missense	Exon 3 of 5	ENSP00000361236.4	Q9H1X1-1
RSPH9	ENST00000890744.1		c.415C>T	p.Arg139Cys	missense	Exon 4 of 6	ENSP00000560803.1
RSPH9	ENST00000372165.8	TSL:2	c.394-24C>T		intron	N/A	ENSP00000361238.4	Q9H1X1-2

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251466

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111994

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000920

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41508

American (AMR)

AF:

0.000196

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67996

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000132

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.10

MutationAssessor

Pathogenic

3.4

PhyloP100

5.7

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.94

MVP

0.87

ClinPred

0.50

GERP RS

5.4

Varity_R

0.58

Mutation Taster

=47/53

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over