NM_080860.4:c.281G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_080860.4(RSPH1):​c.281G>A​(p.Trp94*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RSPH1
NM_080860.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.71

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 21-42486455-C-T is Pathogenic according to our data. Variant chr21-42486455-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 144011.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
RSPH1NM_080860.4 linkc.281G>A p.Trp94* stop_gained Exon 4 of 9 ENST00000291536.8 NP_543136.1 Q8WYR4-1
RSPH1NM_001286506.2 linkc.167G>A p.Trp56* stop_gained Exon 3 of 8 NP_001273435.1 Q8WYR4-2
RSPH1XM_011529786.2 linkc.281G>A p.Trp94* stop_gained Exon 4 of 8 XP_011528088.1
RSPH1XM_005261208.3 linkc.74G>A p.Trp25* stop_gained Exon 2 of 7 XP_005261265.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RSPH1ENST00000291536.8 linkc.281G>A p.Trp94* stop_gained Exon 4 of 9 1 NM_080860.4 ENSP00000291536.3 Q8WYR4-1
RSPH1ENST00000398352.3 linkc.167G>A p.Trp56* stop_gained Exon 3 of 8 5 ENSP00000381395.3 Q8WYR4-2
RSPH1ENST00000493019.1 linkn.341G>A non_coding_transcript_exon_variant Exon 4 of 8 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461020
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726902
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86240
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111240
Other (OTH)
AF:
0.00
AC:
0
AN:
60366
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.408
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 24 Pathogenic:2
-
Genomics England Pilot Project, Genomics England
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jul 01, 2014
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Primary ciliary dyskinesia Pathogenic:1
Jan 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp94*) in the RSPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH1 are known to be pathogenic (PMID: 23993197). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 24518672). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 144011). For these reasons, this variant has been classified as Pathogenic. -

RSPH1-related disorder Pathogenic:1
Mar 23, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The RSPH1 c.281G>A variant is predicted to result in premature protein termination (p.Trp94*). This variant was reported in the compound heterozygous state in a patient with primary ciliary dyskinesia (Onoufriadis et al. 2014. PubMed ID: 24518672; Fassad et al. 2019. PubMed ID: 31879361). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in RSPH1 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
0.62
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
39
DANN
Uncertain
0.99
Eigen
Pathogenic
0.80
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.98
D
PhyloP100
6.7
Vest4
0.41
GERP RS
5.4
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs587777635; hg19: chr21-43906565; API