rs869320683

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PP3_ModeratePP5_Very_StrongBS2_Supporting

The NM_001010892.3(RSPH4A):c.921+3_921+6delAAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000461 in 1,562,432 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 2 hom. )

Consequence

RSPH4A
NM_001010892.3 splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.37

Publications

7 publications found

Variant links:

Genes affected

RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

RSPH4A Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 11
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 6-116623001-TAGTA-T is Pathogenic according to our data. Variant chr6-116623001-TAGTA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 88863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 link	c.921+3_921+6delAAGT		splice_region_variant, intron_variant	Intron 2 of 5	ENST00000229554.10	NP_001010892.1	Q5TD94-1B3KTA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH4A	ENST00000229554.10 link	c.921_921+3delAGTA	p.Ile307MetfsTer8	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 6	1	NM_001010892.3	ENSP00000229554.5	Q5TD94-1
RSPH4A	ENST00000368581.8 link	c.921_921+3delAGTA	p.Ile307MetfsTer8	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 5	1		ENSP00000357570.4	Q5TD94-3
RSPH4A	ENST00000368580.4 link	c.921_921+3delAGTA	p.Ile307AlafsTer28	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 5	5		ENSP00000357569.4	Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000320

AC:

AN:

249652

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1410092

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

704904

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32360

American (AMR)

AF:

0.000425

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

85158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1064996

Other (OTH)

AF:

0.000136

AC:

AN:

58750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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:

0.000276

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.00248

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.00

Hom.:

Bravo

AF:

0.000748

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 11

Pathogenic:3

Apr 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 04, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Pathogenic:3

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 2 of the RSPH4A gene. It does not directly change the encoded amino acid sequence of the RSPH4A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs547686445, gnomAD 0.02%). This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23798057). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88863). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 2 skipping, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23798057). For these reasons, this variant has been classified as Pathogenic. -

Jan 12, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.921+3_921+6delAAGT intronic pathogenic mutation, located in intron 2 of the RSPH4A gene, results from a deletion of 4 nucleotides within intron 2 of the RSPH4A gene. This mutation was first identified in the homozygous state in 8 individuals from 6 unrelated families with primary ciliary dyskinesia, without situs abnormalities; in vitro functional studies found this intronic mutation results in an out of frame deletion of exon 2 and a premature stop codon (p.Y230Qfs*8) (Daniels ML et al. Hum. Mutat., 2013 Oct;34:1352-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Apr 26, 2018

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Jul 18, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PS4_moderate, PVS1 -

Jul 22, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 34513534, 31589614, 35753512, 33670432, 36768259, 23798057) -

RSPH4A-related disorder

Pathogenic:1

Aug 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RSPH4A c.921+3_921+6delAAGT variant is predicted to result in an intronic deletion. This variant has been reported in the homozygous and compound heterozygous state in 9 individuals with primary ciliary dyskinesia from 7 unrelated families with Puerto Rican ancestry (Daniels et al. 2013. PubMed ID: 23798057). Function analysis of this variant showed an out-of-frame deletion of exon 2 leading to a premature protein termination (p.Tyr230Glnfs*8) (Daniels et al. 2013. PubMed ID: 23798057). In summary, this variant is interpreted as pathogenic. -

Kartagener syndrome

Pathogenic:1

Sep 03, 2015

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.4

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 1

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