chr6-43645196-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_152732.5(RSPH9):c.98T>C(p.Met33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

RSPH9
NM_152732.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.412

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: 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03819874).

BP6

Variant 6-43645196-T-C is Benign according to our data. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069. Variant chr6-43645196-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 575069.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH9	NM_152732.5 link	c.98T>C	p.Met33Thr	missense_variant	Exon 1 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.98T>C	p.Met33Thr	missense_variant	Exon 1 of 5	1	NM_152732.5	ENSP00000361236.4		Q9H1X1-1
RSPH9	ENST00000372165.8 link	c.98T>C	p.Met33Thr	missense_variant	Exon 1 of 6	2		ENSP00000361238.4		Q9H1X1-2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250482

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461604

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33476

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000935

AC:

104

AN:

1111982

Other (OTH)

AF:

0.0000828

AC:

AN:

60392

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

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:

0.0000788

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41472

American (AMR)

AF:

0.000262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000142

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:1

Mar 05, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 33 of the RSPH9 protein (p.Met33Thr). This variant is present in population databases (rs374043705, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RSPH9-related conditions. ClinVar contains an entry for this variant (Variation ID: 575069). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.5

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0094

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.40

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.76

N;N

PhyloP100

-0.41

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.025

Sift

Benign

0.34

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0

.;B

Vest4

0.13

MVP

0.28

MPC

1.0

ClinPred

0.015

GERP RS

-0.74

PromoterAI

0.077

Neutral

(source)

Varity_R

0.075

gMVP

0.59

Mutation Taster

=90/10

polymorphism

(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