chr6-158986423-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_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, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.87

Publications

1 publications found

Variant links:

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

RSPH3 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, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031924.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RSPH3	NM_031924.8	MANE Select	c.205-2A>G	splice_acceptor intron	N/A	NP_114130.4
RSPH3	NM_001346418.1		c.631-3735A>G	intron	N/A	NP_001333347.1	Q86UC2-2
RSPH3	NR_144434.1		n.842-2A>G	splice_acceptor intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.205-2A>G	splice_acceptor intron	N/A	ENSP00000356036.1	A0A0C4DFU3
RSPH3	ENST00000884885.1		c.205-2A>G	splice_acceptor intron	N/A	ENSP00000554944.1
RSPH3	ENST00000449822.6	TSL:2	c.205-3735A>G	intron	N/A	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

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:

AN:

240528

AF XY:

0.0000615

show subpopulations

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:

AN:

1451028

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

722132

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32670

American (AMR)

AF:

0.0000970

AC:

AN:

41242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25472

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

84392

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.000352

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1108754

Other (OTH)

AF:

0.0000334

AC:

AN:

59908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000394

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41574

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.0000434

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 32 (4)

RSPH3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Benign

0.95

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

PhyloP100

3.9

GERP RS

5.3

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

Publications

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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