NM_080860.4:c.275-2A>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_080860.4(RSPH1):c.275-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000704 in 1,611,742 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 1 hom. )

Consequence

RSPH1
NM_080860.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 6.80

Publications

14 publications found

Variant links:

Genes affected

RSPH1 (HGNC:12371): (radial spoke head component 1) This gene encodes a male meiotic metaphase chromosome-associated acidic protein. This gene is expressed in tissues with motile cilia or flagella, including the trachea, lungs, airway brushings, and testes. Mutations in this gene result in primary ciliary dyskinesia-24. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

RSPH1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 24
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 21-42486463-T-G is Pathogenic according to our data. Variant chr21-42486463-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 66990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4 link	c.275-2A>C	splice_acceptor_variant, intron_variant	Intron 3 of 8	ENST00000291536.8	NP_543136.1	Q8WYR4-1
RSPH1	NM_001286506.2 link	c.161-2A>C	splice_acceptor_variant, intron_variant	Intron 2 of 7		NP_001273435.1	Q8WYR4-2
RSPH1	XM_011529786.2 link	c.275-2A>C	splice_acceptor_variant, intron_variant	Intron 3 of 7		XP_011528088.1
RSPH1	XM_005261208.3 link	c.68-2A>C	splice_acceptor_variant, intron_variant	Intron 1 of 6		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH1	ENST00000291536.8 link	c.275-2A>C	splice_acceptor_variant, intron_variant	Intron 3 of 8	1	NM_080860.4	ENSP00000291536.3	Q8WYR4-1
RSPH1	ENST00000398352.3 link	c.161-2A>C	splice_acceptor_variant, intron_variant	Intron 2 of 7	5		ENSP00000381395.3	Q8WYR4-2
RSPH1	ENST00000493019.1 link	n.335-2A>C	splice_acceptor_variant, intron_variant	Intron 3 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.000735

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000370

AC:

AN:

251452

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000712

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000732

AC:

1068

AN:

1459644

Hom.:

Cov.:

AF XY:

0.000688

AC XY:

500

AN XY:

726380

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33410

American (AMR)

AF:

0.000268

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000893

AC:

991

AN:

1110050

Other (OTH)

AF:

0.000929

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.000441

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41384

American (AMR)

AF:

0.000720

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68030

Other (OTH)

AF:

0.00191

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000595

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 24

Pathogenic:8

Mar 27, 2025

Department of Human Genetics, Hannover Medical School

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG: PVS1, PM2_Supporting, PM3 -

Sep 05, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 23, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 20, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This RSPH1 canonical splice variant has been reported in the homozygous or compound heterozygous state in individuals and families with primary ciliary dyskinesia. The variant (rs151107532) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 67/152098 total alleles; 0.044%; no homozygotes). It has been reported in ClinVar (Variation ID 66990). This variant destroys a canonical splice acceptor site, is predicted to cause abnormal gene splicing, and has supporting functional evidence. We consider c.275-2A>C in RSPH1 to be pathogenic. -

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RSPH1 c.275-2A>C variant (rs151107532) is reported in the literature in numerous homozygous or compound heterozygous individuals affected with primary ciliary dyskinesia (Fassad 2020, Kott 2013, Onoufriadis 2014, Tinoco 2023). This variant is found in the non-Finnish European population with an allele frequency of 0.067% (87/129,160 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice acceptor site of intron 3, which is likely to negatively impact gene function. Consistent with this, functional studies show this variant leads to exon skipping and is associated with reduced protein expression (Kott 2013, Onoufriadis 2014). Based on available information, this variant is considered to be pathogenic. References: Fassad MR et al. Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. J Med Genet. 2020 May;57(5):322-330. PMID: 31879361. Kott E et al. Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. Am J Hum Genet. 2013 Sep 5;93(3):561-70. PMID: 23993197. Onoufriadis A et al. Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects. Hum Mol Genet. 2014 Jul 1;23(13):3362-74. PMID: 24518672. Tinoco EM et al. Primary Ciliary Dyskinesia in a Portuguese Bronchiectasis Outpatient Clinic. Genes (Basel). 2023 Feb 21;14(3):541. PMID: 36980814. -

Nov 06, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Pathogenic:2

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 3 of the RSPH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs151107532, gnomAD 0.07%). Disruption of this splice site has been observed in individuals with primary ciliary dyskinesia, many of whom were homozygous for this variant (PMID: 23993197, 24518672, 24568568). ClinVar contains an entry for this variant (Variation ID: 66990). Studies have shown that disruption of this splice site results in skipping of exons 4-5 or exons 4-6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23993197, 24568568). For these reasons, this variant has been classified as Pathogenic. -

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Oct 30, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 34670123, 34758253, 31772028, 31879361, 31980526, 32253119, 35728977, 28793908, 25186273, 24568568, 23993197, 24518672, 36980814) -

Jun 18, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RSPH1-related disorder

Pathogenic:1

May 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RSPH1 c.275-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous state and compound heterozygous state in multiple unrelated individuals affected with primary ciliary dyskinesia (PCD) (Kott et al. 2013. PubMed ID: 23993197; Knowles et al. 2014. PubMed ID: 24568568; Onoufriadis et al. 2014. PubMed ID: 24518672). In vitro RT-PCR analysis showed that the c.275-2A>C variant leads to the skipping of either exons 4-5 or exons 4-6, resulting in a frameshift and premature protein termination (Kott et al. 2013. PubMed ID: 23993197; Knowles et al. 2014. PubMed ID: 24568568). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in RSPH1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Kartagener syndrome

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

PhyloP100

6.8

GERP RS

5.4

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.84

Position offset: -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