rs142800871

Variant names:

• chr6-158986423-T-C
• rs142800871
• NM_031924.8:c.205-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_031924.8(RSPH3):​c.205-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000131 in 1,603,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RSPH3 NM_031924.8 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.87
• Publications: 1 publications found

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

RSPH3 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 32

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of 22, new splice context is: cggacggcctgattctctAGagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 6-158986423-T-C is Pathogenic according to our data. Variant chr6-158986423-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 209010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH3	NM_031924.8	c.205-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 7	ENST00000367069.7	NP_114130.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7	c.205-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 7	1	NM_031924.8	ENSP00000356036.1
RSPH3	ENST00000449822.6	c.205-3735A>G		intron_variant	Intron 2 of 5	2		ENSP00000393195.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000457 AC: 11 AN: 240528 AF XY: 0.0000615

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.0000960

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.000517

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1451028 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10 AN XY: 722132

African (AFR) AF: 0.0000306 AC: 1 AN: 32670

American (AMR) AF: 0.0000970 AC: 4 AN: 41242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 84392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5682

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108754

Other (OTH) AF: 0.0000334 AC: 2 AN: 59908

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74498

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 32 Pathogenic:2

Feb 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 209010). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 26073779). This variant is present in population databases (rs142800871, gnomAD 0.01%). This sequence change affects an acceptor splice site in intron 2 of the RSPH3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RSPH3 are known to be pathogenic (PMID: 26073779). -

Jul 02, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

RSPH3-related disorder Pathogenic:1

Jul 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RSPH3 c.631-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous states in individuals with primary ciliary dyskinesia (Jeanson et al. 2015. PubMed ID: 26073779). This variant is reported in 0.0096% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice acceptor site in RSPH3 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Benign	0.95
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		3.9
GERP RS		5.3
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 20
DS_AL_spliceai		0.48		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142800871; hg19: chr6-159407455;