chr21-42485807-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3PP5_Moderate

The NM_080860.4(RSPH1):c.366-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RSPH1
NM_080860.4 splice_region, intron

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.88

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 21-42485807-G-T is Pathogenic according to our data. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42485807-G-T is described in CliVar as Pathogenic. Clinvar id is 66988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4 link	c.366-3C>A	splice_region_variant, intron_variant	Intron 4 of 8	ENST00000291536.8	NP_543136.1	Q8WYR4-1
RSPH1	NM_001286506.2 link	c.252-3C>A	splice_region_variant, intron_variant	Intron 3 of 7		NP_001273435.1	Q8WYR4-2
RSPH1	XM_011529786.2 link	c.366-3C>A	splice_region_variant, intron_variant	Intron 4 of 7		XP_011528088.1
RSPH1	XM_005261208.3 link	c.159-3C>A	splice_region_variant, intron_variant	Intron 2 of 6		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH1	ENST00000291536.8 link	c.366-3C>A	splice_region_variant, intron_variant	Intron 4 of 8	1	NM_080860.4	ENSP00000291536.3	Q8WYR4-1
RSPH1	ENST00000493019.1 link	n.989C>A	non_coding_transcript_exon_variant	Exon 4 of 8	2
RSPH1	ENST00000398352.3 link	c.252-3C>A	splice_region_variant, intron_variant	Intron 3 of 7	5		ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 24

Pathogenic:1

Sep 05, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Primary ciliary dyskinesia

Pathogenic:1

Jul 28, 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 66988). This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23993197). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the RSPH1 gene. It does not directly change the encoded amino acid sequence of the RSPH1 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

2.9

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.44

Position offset: -3

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over